U.S. patent application number 14/189555 was filed with the patent office on 2015-06-11 for method of making 1-(acyloxy)-alkyl carbamate compounds.
This patent application is currently assigned to XENOPORT, INC.. The applicant listed for this patent is XENOPORT, INC.. Invention is credited to Qunying Dai, Peng Liu, Stephen P. Raillard, Huan Wang, Hao Yin.
Application Number | 20150158809 14/189555 |
Document ID | / |
Family ID | 50288274 |
Filed Date | 2015-06-11 |
United States Patent
Application |
20150158809 |
Kind Code |
A9 |
Wang; Huan ; et al. |
June 11, 2015 |
METHOD OF MAKING 1-(ACYLOXY)-ALKYL CARBAMATE COMPOUNDS
Abstract
Methods of preparing carbamate prodrugs of amine-containing
drugs are provided. Carbonates useful in the synthesis of the
carbamate prodrugs are also provided.
Inventors: |
Wang; Huan; (King of
Prussia, PA) ; Liu; Peng; (King of Prussia, PA)
; Dai; Qunying; (King of Prussia, PA) ; Yin;
Hao; (Vienna, VA) ; Raillard; Stephen P.;
(Mountain View, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
XENOPORT, INC. |
SANTA CLARA |
CA |
US |
|
|
Assignee: |
XENOPORT, INC.
SANTA CLARA
CA
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20140243544 A1 |
August 28, 2014 |
|
|
Family ID: |
50288274 |
Appl. No.: |
14/189555 |
Filed: |
February 25, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61769554 |
Feb 26, 2013 |
|
|
|
Current U.S.
Class: |
558/273 ;
560/129 |
Current CPC
Class: |
C07D 317/64 20130101;
C07C 2601/14 20170501; C07C 269/04 20130101; C07C 235/46 20130101;
C07C 269/04 20130101; C07C 69/96 20130101; C07C 235/60 20130101;
C07C 317/22 20130101; C07C 255/55 20130101; C07D 319/18 20130101;
C07C 271/22 20130101; C07C 68/06 20130101; C07C 69/96 20130101;
C07C 255/57 20130101; C07C 68/06 20130101; C07C 269/00
20130101 |
International
Class: |
C07C 69/96 20060101
C07C069/96; C07C 255/57 20060101 C07C255/57; C07C 269/00 20060101
C07C269/00 |
Claims
1. A method of making a compound of formula (I), or a stereoisomer
thereof, a diastereomer thereof, or a salt of any one of foregoing,
comprising: (A) reacting a compound of formula (II), or a
stereoisomer or a salt thereof, with R.sup.1CO.sub.2H to form a
compound of formula (III); ##STR00072## and (B) reacting the
compound of formula (III), or a stereoisomer or a salt thereof,
with HNR.sup.4aR.sup.4b to form the compound of formula (I):
##STR00073## wherein: each of R.sup.1 and R.sup.2 is independently
C.sub.1-4 alkyl; R.sup.3 is H or C.sub.1-4 alkyl;
HNR.sup.4aR.sup.4b is a drug molecule having an amino moiety;
R.sup.4a and R.sup.4a are groups of the drug molecule attached to
the amino moiety; each of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d,
and R.sup.5e is independently selected from H, halo, C.sub.1-4
alkyl, halo C.sub.1-4 alkyl, phenyl, --C(O)O--C.sub.1-4 alkyl,
--C(O)--C.sub.1-4 alkyl, --S(O)--C.sub.1-4 alkyl, CN,
--C(O)--NR.sup.6aR.sup.6b, substituted or unsubstituted C.sub.1-4
alkoxy, and substituted or unsubstituted phenoxy; provided that at
least one of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and R.sup.5e
is other than H; or any two adjacent R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e are joined together to form a carbocycle or
heterocycle; each R.sup.6a and R.sup.6b is independently H, or
C.sub.1-4 alkyl; or R.sup.6a and R.sup.6b together with N they are
attached to form heterocycle; and X is a leaving group.
2. The method of claim 1, wherein X is halo.
3. The method of claim 1, wherein X is Cl.
4. The method of claim 1, wherein reaction step (A) occurs in a
solvent.
5. The method of claim 4, wherein the solvent is selected from the
group consisting of heptane, xylene, toluene, N-methylpyrrolidine,
N,N-diisopropylamine, dimethyl formamide, dimethyl sulfoxide,
diphenyl ether, and combinations thereof.
6. The method of claim 1, wherein reaction step (A) occurs at a
temperature from about 50.degree. C. to about 120.degree. C.
7. The method of claim 1, wherein reaction step (A) occurs in the
presence of a metal oxide.
8. The method of claim 1, wherein the reaction step (A) occurs in
the presence of a metal alkanoate or a metal salt of
R.sup.1CO.sub.2H.
9. The method of claim 1, wherein reaction step (A) occurs in the
presence of R.sup.1C(O)--O--C(O)R.sup.1.
10. The method of claim 1, wherein reaction step (A) occurs in the
presence of a tetraalkylammonium salt.
11. The method of claim 1, wherein reaction step (A) occurs in the
presence of an organic base.
12. The method of claim 1, wherein reaction step (B) occurs in a
solvent selected from the group consisting of heptane, xylene,
toluene, dialkyl ether, cyclic ethers, dimethyl formamide, dimethyl
sulfoxide, water, acetonitrile, ethyl acetate, and combinations
thereof.
13. The method of claim 1, wherein reaction step (B) occurs at a
temperature from about 0.degree. C. to about 50.degree. C.
14. The method of claim 1, wherein reaction step (B) occurs in the
presence of a base.
15. The method of claim 1, wherein R.sup.1 is i-Pr; R.sup.2 is Me
or i-Pr; and R.sup.3 is H.
16. The method of claim 1, wherein one or more of R.sup.5a,
R.sup.5b, R.sup.5c, R.sup.5d, and R.sup.5e is independently halo,
C.sub.1-4 alkyl, --C(O)O--C.sub.1-4 alkyl, or substituted or
unsubstituted alkoxy, and the rest are H.
17. The method of claim 1, wherein the drug molecule
HNR.sup.4aR.sup.4b is selected from: acebutalol, albuterol,
alprenolol, atenolol, bunolol, bupropion, butopamine, butoxamine,
carbuterol, cartelolol, colterol, deterenol, dexpropanolol,
diacetolol, dobutamine, exaprolol, exprenolol, fenoterol,
fenyripol, labotolol, levobunolol, metolol, metaproterenol,
metoprolol, nadolol, pamatolol, penbutalol, pindolol, pirbuterol,
practolol, prenalterol, primidolol, prizidilol, procaterol,
propanolol, quinterenol, rimiterol, ritodrine, solotol, soterenol,
sulfiniolol, sulfinterol, sulictidil, tazaolol, terbutaline,
timolol, tiprenolol, tipridil, tolamolol, thiabendazole,
albendazole, albutoin, alendronate, alinidine, alizapride,
amiloride, aminorex, aprinocid, cambendazole, cimetidine,
cisapride, clonidine, cyclobenzadole, delavirdine, efegatrin,
etintidine, fenbendazole, fenmetazole, flubendazole, fludorex,
gabapentin, icadronate, lobendazole, mebendazole, metazoline,
metoclopramide, methylphenidate, mexiletine, neridronate,
nocodazole, oxfendazole, oxibendazole, oxmetidine, pamidronate,
parbendazole, pramipexole, prazosin, pregabalin, procainamide,
ranitidine, tetrahydrazoline, tiamenidine, tinazoline, tiotidine,
tocainide, tolazoline, tramazoline, xylometazoline,
dimethoxyphenethylamine,
n-[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1-yl]acetyl-3(R)-methyl-.be-
ta.-alanine, adrenolone, aletamine, amidephrine, amphetamine,
aspartame, bamethan, betahistine, carbidopa, clorprenaline,
chlortermine, dopamine, L-dopa, ephrinephrine, etryptamine,
fenfluramine, methyldopamine, norepinephrine, enviroxime,
nifedipine, nimodipine, triamterene, pipedemic acid and similar
compounds,
1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-napthyridine-3-c-
arboxylic acid and
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazinyl)-3-quinolinecarbo-
xylic acid, theprubicin, deoxyspergualin, seglitide, nebracetam,
benanomicin B, eremomycin, thrazarine, tosufloxacin, baogongteng A,
angiopeptin, boholmycin, ravidomycin, tageflar, orienticins,
amphotericin B, tiamdipine, doxorubicin, lysobactin, mofegiline,
octreotide, oxolide, amikacin, phospholine, nuvanil, cispentacin,
chlorotetain, remacemide, ramoplanins, janthinomycins, mersacidin,
droxidopa, helvecardin A, helvecardin B, rilmazafone, vigabatrin,
amlodipine, (R)-(+)-amlodipine, mideplanin, milnacipran,
pranedipine, olradipine, deoxymethylspergualin, fudosteine,
trovafloxacin, ceranapril, restricticin, idarubicin, arbekacin,
giracodazole, poststatin, pazufloxacin, D-cycloserine, ovothiol A,
ceftizoxime, icatibant, p-iodorubidazone, aladapcin, dalargin,
seproxetine, pradimicin E, pradimicin FA-2, tafenoquine,
sampatrilat, ruboxyl, dactimicin, alatrofloxacin, galarubicin,
metaraminol, exatecan, squalamine, paromomycin, leustroducsin A,
leustroducsin B, leustroducsin C, lanicemine, azoxybacilin,
tetrafibricin, pixantrone, ziconotide, garomefrine, spinorphin,
doripenem, alestramustine, seraspenide, safingol, aminolevulinic
acid, pelagiomicin C, styloguanidine, L-4-oxalysine, eglumegad,
rhodopeptins, mycestericin E, midaxifylline, anisperimus, lagatide,
ibutamoren, oritavancin, ecenofloxacin, metyrosine, methyldopa,
baclofen, tranylcypromine, micronomicin, zorubicin, epirubicin,
gilatide, epithalon, cystamine, pluraflavin A, pluraflavin B,
pasireotide, caprazamycin, barusiban, spisulosine,
21-aminoepothilone B, capsavanil, olcegepant, sulphostin,
lobophorin A, papuamide A, papuamide B, cystocin, deoxynegamycin,
galnon, pyloricidin B, brasilicardin A, neramexane, kaitocephalin,
icofungipen, aliskiren, capromorelin, histaprodifen, donitriptan,
cambrescidins, tipifarnib, tabimorelin, belactosin A, belactosin C,
circinamide, targinine, sulphazocine, nepicastat, oseltamivir,
hydrostatin A, butabindide, netamiftide, memantine, fluvoxamine,
deferoxamine, tranexamic acid, fortimicin A, cefaclor, lisinopril,
ubestatin, cefminox, aspoxicillin, cefcanel, cefcanel daloxate,
olamufloxacin, R-(+)-aminoindane, gemifloxacin, kahalalide F,
palau'amine, examorelin, leustroducsin H, sabarubicin, amifostine,
L-homothiocitrulline, L-thiocitrulline, impentamine, neboglamine,
amselamine, cetefloxacin, cyclothialidine, fluvirucin B2,
loracarbef, cefprozil, sperabillins, milacainide, avizafone,
.alpha.-methyltryptophan, cytaramycin, lanomycin, decaplanin,
eflornithine, L-histidinol, tuftsin, kanamycin, amthamine,
sitafloxacin, leurubicin, amantadine, isodoxorubicin, gludopa,
bactobolin, esafloxacin, tabilautide, lazabemide, enalkiren,
amrubicin, daunorubicin, mureidomycins, pyridazomycin, cimaterol,
(+)-isamoltan, N-desmethylmilameline, noberastine, fosopamine,
adaprolol, pradimicin B, amosulalol, xamoterol, boholmycin,
risotilide, indeloxazine, denopamine, parodilol, utibapril,
nardeterol, biemnidin, sparfloxacin, sibanomicin, tianeptine,
oberadilol, methoctramine, sezolamide, anabasine, zilpaterol,
zabiciprilat, enkastins, ulifloxacin, (+)-sotalol,
deoxynojirimycin, altromycin A, altromycin C, dorzolamide,
fepradinol, delapril, ciprofloxacin, balofloxacin, mepindolol,
berlafenone, ramipril, dopexamine, dilevalol, (-)-nebivolol,
duramycin, enalapril, meluadrine, zelandopam, voglibose,
sertraline, carvedilol, pafenolol, paroxetine, fluoxetine,
phendioxan, salmeterol, solpecainol, repinotan, bambuterol,
safinamide, tilisolol, 7-oxostaurosporine, caldaret, sertraline,
cilazapril, benazepril, prisotinol, gatifloxacin, ovothiol B,
adaprolol, tienoxolol, fluparoxan, alprenoxime, efegatran,
pradimicin, salbostatin, ersentilide, (S)-noremopamil, esperamicin
A1, batoprazine, ersentilide, osutidine, quinapril, dihydrexidine,
argiopine, pradimicin D, frovatriptan, hispidospermidin, silodosin,
michellamine B, sibenadet, tetrindol, talibegron, topixantrone,
nortopixantrone, tecalcet, buteranol, .alpha.-methylepinephrine,
nornicotine, thiofedrine, lenapenem, imidapril, epibatidine,
premafloxacin, socorromycin, trandolapril, tamsulosin,
dirithromycin, inogatran, vicenistatin, immepyr, immepip, balanol,
orbifloxacin, maropitant, dabelotine, lerisetron, ertapenem,
nolomirole, moxifloxacin, vofopitant, halofuginone, melagatran,
ximelagatran, fasudil, isofagomine, pseudoephedrine, propafenone,
celiprolol, carteolol, penbutolol, labetalol, acebutolol,
reproterol, rimoterol, amoxapine, maprotiline, viloxazine,
protriptyline, nortriptyline, desipramine, oxprenolol, propranolol,
ketamine, butofilolol, flecainide, tulobuterol, befunolol,
immucillin-H, vestipitant, cinacalcet, lapatinib, desloratadine,
ladostigil, vildagliptin, tulathromycin B, becampanel, salbutamol,
delucemine, solabegron, paroxetine, gaboxadol, telavancin,
ralfinamide, tomoxetine, dalbavancin, elarofiban, ferulinolol,
fenoldopam, sumanirole, sarizotan, brinzolamide, pradofloxacin,
garenoxacin, reboxetine, ezlopitant, palindore, nebivolol,
dinapsoline, proxodolol, repinotan, demexiptiline, mitoxantrone,
norfloxacin, dilevalol, nipradilol, esmolol, ibopamine, troxipide,
arotinolol, formoterol, bopindolol, cloranolol, mefloquine,
perindopril, mabuterol, bisoprolol, bevantolol, betaxolol,
tertatolol, enoxacin, lotrafiban, moexipril, droxinavir,
adrogolide, alniditan, tigecycline, lubazodone, meropenem,
temocapril, napsamycins, (-)-cicloprolol, ecteinascidins,
alprafenone, landiolol, tirofiban, noberastine, rasagiline,
setazindol, picumeterol, arbutamine, mecamylamine, delfaprazine,
imidapril, midafotel, manzamines, binospirone, duloxetine, and
litoxetine.
18. The method of claim 1, wherein R.sup.4a is H; and R.sup.4b is
selected from ##STR00074##
19. The method of claim 18, wherein R.sup.7 is Cl or F.
20. The method of claim 1, wherein the compound of formula (I) is a
compound according to formula (IVa), (IVb), (IVc), (IVd), or (IVe):
##STR00075## or a salt thereof.
21. A compound according to formula (III): ##STR00076## a
stereoisomer thereof, a diastereomer thereof; or a salt of any one
of foregoing; wherein each of R.sup.1 and R.sup.2 is independently
C.sub.1-4 alkyl; R.sup.3 is H or C.sub.1-4 alkyl; each of R.sup.5a,
R.sup.5b, R.sup.5c, R.sup.5d, or R.sup.5e is independently selected
from a group consisting of H, halo, C.sub.1-4 alkyl, halo C.sub.1-4
alkyl, phenyl, --C(O)O--C.sub.1-4 alkyl, --C(O)--C.sub.1-4 alkyl,
--S(O)--C.sub.1-4 alkyl, CN, --C(O)--NR.sup.6aR.sup.6b, substituted
or unsubstituted C.sub.1-4 alkoxy, and substituted or unsubstituted
phenoxy; and each of R.sup.6a and R.sup.6b is independently H, or
C.sub.1-4 alkyl; or R.sup.6a and R.sup.6b together with N they are
attached to form heterocycle; provided that at least one of
R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and R.sup.5e is other than
H; or any two of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and
R.sup.5e form O--CH.sub.2--O--, or
--O--CH.sub.2--CH.sub.2--O--.
22. The compound of claim 21, wherein R.sup.1 is i-Pr; R.sup.2 is
methyl or i-Pr; and R.sup.3 is H.
23. The compound of claim 21, wherein one or more of R.sup.5a,
R.sup.5b, R.sup.5c, R.sup.5d, and R.sup.5e is halo, and the rest
are H.
24. The compound of claim 21, wherein one of R.sup.5a, R.sup.5b,
R.sup.5c, R.sup.5d, and R.sup.5e is Me, Et, --C(O)OMe, --C(O)OEt,
--OMe, --CF.sub.3, CN, --C(O)Me, --S(O)Me, --C(O)NH.sub.2,
--C(O)NMe.sub.2, and the rest are H.
25. The compound of claim 21, wherein the compound is a compound
according to formula (VIIa), (VIIb), (VIIc), (VIId), (VIIe),
(VIIf), (VIIg), or (VIIh): ##STR00077## a stereoisomer thereof, a
diastereomer thereof; or a salt of any one of foregoing.
26. The compound of claim 21, wherein the compound is a compound
according to formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe),
or (VIIIf): ##STR00078## a stereoisomer thereof, a diastereomer
thereof; or a salt of any one of foregoing.
27. The compound of claim 21, wherein the compound is a compound
according to formula (IXa), (IXb), (IXc), (IXd), (IXe), (IXf),
(IXg), or (IXh): ##STR00079## a stereoisomer thereof, a
diastereomer thereof; or a salt of any one of foregoing.
28. The compound of claim 21, wherein the compound is a compound
according to formula (Xa), (Xb), (Xc), (Xd), (Xe), or (Xf):
##STR00080## a stereoisomer thereof, a diastereomer thereof; or a
salt of any one of foregoing.
29. The compound of claim 21, wherein the compound is a compound
according to formula (XIa), (XIb), (XIc), (XId), (XIe), (XIf),
(XIg), or (XIh): ##STR00081## a stereoisomer thereof, a
diastereomer thereof; or a salt of any of the foregoing.
30. The compound of claim 21, wherein the compound is a compound
according to formula (XIIa), (XIIb), (XIIc), (XIId), (XIIe), or
(XIIf): ##STR00082## a stereoisomer thereof, a diastereomer
thereof; or a salt thereof.
31. The compound of claim 21, wherein the compound is a compound
according to formula (XIIIa), (XIIIb), (XIIIc), (XIIId), (XIIIe),
(XIIIf), (XIIIg), or (XIIIh) ##STR00083## a stereoisomer thereof, a
diastereomer thereof; or a salt of any of the foregoing.
32. The compound of claim 21, wherein the compound is a compound
according to formula (XIVa), (XIVb), (XIVc), (XIVd), (XIVe), or
(XIVf): ##STR00084## a stereoisomer thereof, a diastereomer
thereof; or a salt of any of the foregoing.
33. The compound of claim 21, wherein the compound is a compound
according to formula (XVa), (XVb), (XVc), (XVd), (XVe), or (XVf):
##STR00085## a stereoisomer thereof, a diastereomer thereof; or a
salt thereof.
34. The compound of claim 21, wherein the compound is a compound
according to formula (XVIa), (XVIb), (XVIc), (XVId), (XVIe), or
(XVIf): ##STR00086## a stereoisomer thereof, a diastereomer
thereof; or a salt thereof.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of the filing date of
U.S. Provisional Application No. 61/769,554, filed Feb. 26, 2013,
entitled METHOD OF MAKING 1-(ACYLOXY)-ALKYL CARBAMATE COMPOUNDS,
the contents of which are herein incorporated by reference.
FIELD
[0002] Provided herein are novel methods useful for preparation of
1-(acyloxy)-alkyl carbamate prodrugs of amino containing drug
compounds. Also provided are compositions of novel compounds useful
for the preparation of the carbamate prodrugs.
BACKGROUND
[0003] Gabapentin ([1-(aminomethyl)cyclohexyl]acetic acid) is an
FDA approved drug that is marketed for the treatment of
post-herpetic neuralgia and epilepsy. Gabapentin suffers from poor
oral bioavailability, which is primarily due to the fact that it is
absorbed by a saturable active transport mechanism in the small
intestine. Gabapentin also has a very short half life in vivo, and
to maintain therapeutic levels in the body, frequent dosing is
required.
[0004] The oral bioavailability of certain drugs can be improved by
conversion to prodrugs. Certain prodrugs are derivatives of the
parent drug in which a functional group is "masked" by a promoiety.
Following administration to a patient, the prodrug is metabolised
to release the parent drug.
[0005] The acyloxyalkoxylcarbonyl functionality is an example of a
promoiety that has been used to functionalize amino containing
drugs such as gabapentin.
1-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid is a 1-(acyloxy)-alkyl carbamate prodrug of gabapentin
that has utility in the treatment of epilepsy (WO 02/100347), pain
(WO 02/100347), particularly neuropathic pain (including
post-herpetic neuralgia and diabetic peripheral neuropathy) or pain
associated with irritable bowel syndrome, anxiety (WO 02/100347),
particularly general anxiety disorder, alcohol dependency or
ethanol withdrawal syndrome (WO 02/100347), restless legs syndrome
(WO 2005/027850), migraine prophylaxis (WO 2008/073257),
fibromyalgia (WO 2008/073257), hot flashes (WO 2004/089289),
particularly hot flashes associated with the menopause and
essential tremor (Patent Application claiming priority from U.S.
Provisional Application No. 61/158,065).
[0006] Methods of preparing 1-(acyloxy)-alkyl carbamate prodrugs
are disclosed in WO 02/100347, WO 03/077902, WO 03/104184, WO
2005/010011 and WO 2005/066122 (all assigned to Xenoport, Inc.), WO
2010/017504 (assigned to Xenoport, Inc. and Glaxo Group Limited),
and U.S. Pat. No. 4,760,057, U.S. Pat. No. 4,916,230 and U.S. Pat.
No. 5,684,018 (all assigned to Merck & Co. Ltd.).
SUMMARY
[0007] There is still a clear unmet need for improved methods for
preparation of the carbamate prodrugs. The compounds, compositions,
and methods of preparation described herein are directed toward
this end.
[0008] Provided herein are novel methods of preparation of
1-(acyloxy)-alkyl carbamate prodrugs of amino containing drug
molecules or drug compounds.
[0009] In certain aspects, provided herein are novel methods of
preparation of 1-(acyloxy)-alkyl carbamate prodrugs of gabapentin
and related compounds.
[0010] In certain aspect, the present disclosure provides a method
of making a compound of formula (I), or a stereoisomer thereof, a
diastereomer thereof, or a salt of any one of foregoing,
comprising:
[0011] (A) reacting a compound of formula (II), or a stereoisomer
or a salt thereof, with R.sup.1CO.sub.2H to form a compound of
formula (III);
##STR00001##
and
[0012] (B) reacting the compound of formula (III), or a
stereoisomer or a salt thereof, with HNR.sup.4aR.sup.4b to form the
compound of formula (I)
##STR00002##
wherein:
[0013] each of R.sup.1 and R.sup.2 is independently C.sub.1-4
alkyl;
[0014] R.sup.3 is H or C.sub.1-4 alkyl;
[0015] HNR.sup.4aR.sup.4b is a drug molecule having an amino
moiety;
[0016] R.sup.4a and R.sup.4a are groups of the drug molecule
attached to the amino moiety;
[0017] each of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and R.sup.5e
is independently selected from H, halo, C.sub.1-4 alkyl, halo
C.sub.1-4 alkyl, phenyl, --C(O)O--C.sub.1-4 alkyl,
--C(O)--C.sub.1-4 alkyl, --S(O)--C.sub.1-4 alkyl, CN,
--C(O)--NR.sup.6aR.sup.6b, substituted or unsubstituted C.sub.1-4
alkoxy, and substituted or unsubstituted phenoxy;
[0018] each of R.sup.6a and R.sup.6b is independently H, or
C.sub.1-4 alkyl; or R.sup.6a and R.sup.6b together with N they are
attached to form heterocycle;
[0019] provided that at least one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is other than H; or any two adjacent
R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and R.sup.5e are joined
together to form a carbocycle or heterocycle; and
[0020] X is a leaving group.
[0021] In some embodiments, R.sup.4a is H; and R.sup.4b is selected
from:
##STR00003##
[0022] the * indicates the attachment point, and R.sup.7 is Cl or
F.
[0023] In another aspect, the present disclosure provides a
compound according to formula (III):
##STR00004##
[0024] or stereoisomer thereof; or a salt of any one of
foregoing;
[0025] wherein each of R.sup.1 and R.sup.2 is independently
C.sub.1-4 alkyl;
[0026] R.sup.3 is H or C.sub.1-4 alkyl;
[0027] each of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, or R.sup.5e
is independently selected from a group consisting of H, halo,
C.sub.1-4 alkyl, halo C.sub.1-4 alkyl, phenyl, --C(O)O--C.sub.1-4
alkyl, --C(O)--C.sub.1-4 alkyl, --S(O)--C.sub.1-4 alkyl, CN,
--C(O)--NR.sup.6aR.sup.6b, substituted or unsubstituted C.sub.1-4
alkoxy, and substituted or unsubstituted phenoxy;
[0028] each of R.sup.6a and R.sup.6b is independently H, or
C.sub.1-4 alkyl; or R.sup.6a and R.sup.6b together with N they are
attached to form heterocycle;
[0029] provided that at least one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is other than H; or
[0030] any two of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and
R.sup.5e form O--CH.sub.2--O--, or O--CH.sub.2--CH.sub.2--O--.
[0031] In another specific aspect, provided herein are compositions
comprising compounds according to formula (III).
[0032] Other objects and advantages will become apparent to those
skilled in the art from a consideration of the ensuing detailed
description.
DEFINITIONS
Chemical Definitions
[0033] Definitions of specific functional groups and chemical terms
are described in more detail below. The chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Thomas Sorrell, Organic Chemistry, University
Science Books, Sausalito, 1999; Smith and March, March's Advanced
Organic Chemistry, 5.sup.th Edition, John Wiley & Sons, Inc.,
New York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3.sup.rd Edition, Cambridge
University Press, Cambridge, 1987.
[0034] Compounds described herein can comprise one or more
asymmetric centers, and thus can exist in various isomeric forms,
e.g., enantiomers and/or diastereomers. For example, the compounds
described herein can be in the form of an individual enantiomer,
diastereomer or geometric isomer, or can be in the form of a
mixture of stereoisomers, including racemic mixtures and mixtures
enriched in one or more stereoisomer. Isomers can be isolated from
mixtures by methods known to those skilled in the art, including
chiral high pressure liquid chromatography (HPLC) and the formation
and crystallization of chiral salts; or preferred isomers can be
prepared by asymmetric syntheses. See, for example, Jacques et al.,
Enantiomers, Racemates and Resolutions (Wiley Interscience, New
York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel,
Stereochemistry of Carbon Compounds (McGrawHill, N.Y., 1962); and
Wilen, Tables of Resolving Agents and Optical Resolutions p. 268
(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.
1972). The present disclosure additionally encompasses compounds
described herein as individual isomers substantially free of other
isomers, and alternatively, as mixtures of various isomers.
[0035] When a range of values is listed, it is intended to
encompass each value and sub range within the range. For example
"C.sub.1-6 alkyl" is intended to encompass, C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5,
C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4,
C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5,
and C.sub.5-6 alkyl. Similarly, "C.sub.1-4 alkyl" is intended to
encompass a linear or branched saturated hydrocarbon group
containing from 1 to 4 carbon atoms. "C.sub.1-4 alkyl" thus
encompasses methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl and tert butyl.
[0036] The following terms are intended to have the meanings
presented therewith below and are useful in understanding the
description and intended scope of the present disclosure. When
describing the subject matter of the present disclosure, which may
include compounds, pharmaceutical compositions containing such
compounds and methods of using such compounds and compositions, the
following terms, if present, have the following meanings unless
otherwise indicated. It should also be understood that when
described herein any of the moieties defined below may be
substituted with a variety of substituents, and that the respective
definitions are intended to include such substituted moieties
within their scope as set out below. Unless otherwise stated, the
term "substituted" is to be defined as set out below. It should be
further understood that the terms "groups" and "radicals" can be
considered interchangeable when used herein. The articles "a" and
"an" may be used herein to refer to one or to more than one (i.e.
at least one) of the grammatical objects of the article. By way of
example "an analogue" means one analogue or more than one
analogue.
[0037] "Alkyl" refers to a radical of a straight-chain or branched
saturated hydrocarbon group having from 1 to 20 carbon atoms
("C.sub.1-20 alkyl"). In some embodiments, an alkyl group has 1 to
12 carbon atoms ("C.sub.1-12 alkyl"). In some embodiments, an alkyl
group has 1 to 10 carbon atoms ("C.sub.1-10 alkyl"). In some
embodiments, an alkyl group has 1 to 9 carbon atoms ("C.sub.1-9
alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon
atoms ("C.sub.1-8 alkyl"). In some embodiments, an alkyl group has
1 to 7 carbon atoms ("C.sub.1-7 alkyl"). In some embodiments, an
alkyl group has 1 to 6 carbon atoms ("C.sub.1-6 alkyl", also
referred to herein as "lower alkyl"). In some embodiments, an alkyl
group has 1 to 5 carbon atoms ("C.sub.1-5 alkyl"). In some
embodiments, an alkyl group has 1 to 4 carbon atoms ("C.sub.1-4
alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon
atoms ("C.sub.1-3 alkyl"). In some embodiments, an alkyl group has
1 to 2 carbon atoms ("C.sub.1-2 alkyl"). In some embodiments, an
alkyl group has 1 carbon atom ("C.sub.1 alkyl"). In some
embodiments, an alkyl group has 2 to 6 carbon atoms ("C.sub.2-6
alkyl"). Examples of C.sub.1-6 alkyl groups include methyl
(C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl
(C.sub.3), n-butyl (C.sub.4), tertbutyl (C.sub.4), secbutyl
(C.sub.4), isobutyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl
(C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl
(C.sub.5), tertiary amyl (C.sub.5), and n-hexyl (C.sub.6).
Additional examples of alkyl groups include n-heptyl (C.sub.7),
n-octyl (C.sub.8) and the like. Unless otherwise specified, each
instance of an alkyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a
"substituted alkyl") with one or more substituents; e.g., for
instance from 1 to 5 substituents, 1 to 3 substituents, or 1
substituent. In certain embodiments, the alkyl group is
unsubstituted C.sub.1-10 alkyl (e.g., --CH.sub.3). In certain
embodiments, the alkyl group is substituted C.sub.1-10 alkyl.
[0038] The term `halo C.sub.x-y alkyl` as used herein refers to a
C.sub.x-y alkyl group as defined herein wherein at least one
hydrogen atom is replaced with halogen. Examples of halo C.sub.1-3
alkyl groups include fluoroethyl, trifluoromethyl or trifluoroethyl
and the like.
[0039] "Acyl" refers to a radical --C(O)R.sup.20, where R.sup.20 is
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, as defined herein.
"Alkanoyl" is an acyl group wherein R.sup.20 is a group other than
hydrogen. Representative acyl groups include, but are not limited
to, formyl (--CHO), acetyl (--C(.dbd.O)CH.sub.3),
cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl
(--C(.dbd.O)Ph), benzylcarbonyl (--C(.dbd.O)CH.sub.2Ph),
C(O)--C.sub.1-C.sub.8 alkyl,
C(O)--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--C(O)--(CH.sub.2).sub.t(5-10 membered heteroaryl),
C(O)--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--C(O)--(CH.sub.2).sub.t(4-10 membered heterocyclyl), wherein t is
an integer from 0 to 4. In certain embodiments, R.sup.21 is
C.sub.1-C.sub.8 alkyl, substituted with halo or hydroxy; or
C.sub.3-C.sub.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, arylalkyl, 5-10 membered heteroaryl or
heteroarylalkyl, each of which is substituted with unsubstituted
C.sub.1-C.sub.4 alkyl, halo, unsubstituted C.sub.1-C.sub.4 alkoxy,
unsubstituted C.sub.1-C.sub.4haloalkyl, unsubstituted
C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted C.sub.1-C.sub.4
haloalkoxy or hydroxy.
[0040] The term `halo` as used herein refers to fluoro, chloro,
bromo or iodo.
[0041] "Compounds," "compounds of the present disclosure", and
equivalent expressions, are meant to embrace the compounds as
hereinbefore described, in particular compounds according to any of
the Formula herein recited and/or described, which expression
includes the prodrugs, the pharmaceutically acceptable salts, and
the solvates, e.g., hydrates, where the context so permits.
Similarly, reference to intermediates, whether or not they
themselves are claimed, is meant to embrace their salts, and
solvates, where the context so permits.
[0042] These and other examples of substituents are described in
more detail in the Detailed Description, Examples, and claims. The
present disclosure is not intended to be limited in any manner by
the above listing of examples of substituents.
OTHER DEFINITIONS
[0043] "Prodrugs" refers to compounds, including derivatives of the
compounds of the present disclosure, which have cleavable groups
and become by solvolysis or under physiological conditions the
compounds of the present disclosure that are pharmaceutically
active in vivo. Such examples include, but are not limited to,
choline ester derivatives and the like, N-alkylmorpholine esters
and the like. Other derivatives of the compounds of this present
disclosure have activity in both their acid and acid derivative
forms, and in some embodiments the acid sensitive form offers
advantages of solubility, tissue compatibility, or delayed release
in the mammalian organism (see, Bundgard, H., Design of Prodrugs,
pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid
derivatives well known to practitioners of the art, such as, for
example, esters prepared by reaction of the parent acid with a
suitable alcohol, or amides prepared by reaction of the parent acid
compound with a substituted or unsubstituted amine, or acid
anhydrides, or mixed anhydrides. Simple aliphatic or aromatic
esters, amides and anhydrides derived from acidic groups pendant on
the compounds of this disclosure are particular prodrugs. In some
cases it is desirable to prepare double ester type prodrugs such as
(acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
Particularly the C.sub.1 to C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, aryl, C.sub.7-C.sub.12 substituted aryl,
and C.sub.7-C.sub.12 arylalkyl esters of the compounds of the
present disclosure.
[0044] "Solvate" refers to forms of the compound that are
associated with a solvent or water (also referred to as "hydrate"),
usually by a solvolysis reaction. This physical association
includes hydrogen bonding. Conventional solvents include water,
ethanol, acetic acid and the like. The compounds of the present
disclosure may be prepared e.g. in crystalline form and may be
solvated or hydrated. Suitable solvates include pharmaceutically
acceptable solvates, such as hydrates, and further include both
stoichiometric solvates and non-stoichiometric solvates. In certain
instances the solvate will be capable of isolation, for example
when one or more solvent molecules are incorporated in the crystal
lattice of the crystalline solid. "Solvate" encompasses both
solution-phase and isolable solvates. Representative solvates
include hydrates, ethanolates and methanolates.
[0045] It is also to be understood that compounds that have the
same molecular formula but differ in the nature or sequence of
bonding of their atoms or the arrangement of their atoms in space
are termed "isomers". Isomers that differ in the arrangement of
their atoms in space are termed "stereoisomers".
[0046] Stereoisomers that are not mirror images of one another are
termed "diastereomers" and those that are non-superimposable mirror
images of each other are termed "enantiomers". When a compound has
an asymmetric center, for example when it is bonded to four
different groups, a pair of enantiomers is possible. An enantiomer
can be characterized by the absolute configuration of its
asymmetric center and is described by the R- and S-sequencing rules
of Cahn and Prelog, or by the manner in which the molecule rotates
the plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture".
[0047] As used herein, a pure enantiomeric compound is
substantially free from other enantiomers or stereoisomers of the
compound (i.e., in enantiomeric excess). In other words, an "S"
form of the compound is substantially free from the "R" form of the
compound and is, thus, in enantiomeric excess of the "R" form. The
term "enantiomerically pure" or "pure enantiomer" denotes that the
compound comprises more than 75% by weight, more than 80% by
weight, more than 85% by weight, more than 90% by weight, more than
91% by weight, more than 92% by weight, more than 93% by weight,
more than 94% by weight, more than 95% by weight, more than 96% by
weight, more than 97% by weight, more than 98% by weight, more than
98.5% by weight, more than 99% by weight, more than 99.2% by
weight, more than 99.5% by weight, more than 99.6% by weight, more
than 99.7% by weight, more than 99.8% by weight or more than 99.9%
by weight, of the enantiomer. In certain embodiments, the weights
are based upon total weight of all enantiomers or stereoisomers of
the compound.
[0048] As used herein and unless otherwise indicated, the term
"enantiomerically pure R-compound" refers to at least about 80% by
weight R-compound and at most about 20% by weight S-compound, at
least about 90% by weight R-compound and at most about 10% by
weight S-compound, at least about 95% by weight R-compound and at
most about 5% by weight S-compound, at least about 99% by weight
R-compound and at most about 1% by weight S-compound, at least
about 99.9% by weight R-compound or at most about 0.1% by weight
S-compound. In certain embodiments, the weights are based upon
total weight of compound.
[0049] As used herein and unless otherwise indicated, the term
"enantiomerically pure 5-compound" or "S-compound" refers to at
least about 80% by weight S-compound and at most about 20% by
weight R-compound, at least about 90% by weight S-compound and at
most about 10% by weight R-compound, at least about 95% by weight
S-compound and at most about 5% by weight R-compound, at least
about 99% by weight S-compound and at most about 1% by weight
R-compound or at least about 99.9% by weight S-compound and at most
about 0.1% by weight R-compound. In certain embodiments, the
weights are based upon total weight of compound.
[0050] In the compositions provided herein, an enantiomerically
pure compound or a pharmaceutically acceptable salt, solvate,
hydrate or prodrug thereof can be present with other active or
inactive ingredients. For example, a pharmaceutical composition
comprising enantiomerically pure R-compound can comprise, for
example, about 90% excipient and about 10% enantiomerically pure
R-compound. In certain embodiments, the enantiomerically pure
R-compound in such compositions can, for example, comprise, at
least about 95% by weight R-compound and at most about 5% by weight
S-compound, by total weight of the compound. For example, a
pharmaceutical composition comprising enantiomerically pure
S-compound can comprise, for example, about 90% excipient and about
10% enantiomerically pure S-compound. In certain embodiments, the
enantiomerically pure S-compound in such compositions can, for
example, comprise, at least about 95% by weight S-compound and at
most about 5% by weight R-compound, by total weight of the
compound. In certain embodiments, the active ingredient can be
formulated with little or no excipient or carrier.
[0051] The compounds of this disclosure may possess one or more
asymmetric centers; such compounds can therefore be produced as
individual (R)- or (S)-stereoisomers or as mixtures thereof.
[0052] Unless indicated otherwise, the description or naming of a
particular compound in the specification and claims is intended to
include both individual enantiomers and mixtures, racemic or
otherwise, thereof. The methods for the determination of
stereochemistry and the separation of stereoisomers are well-known
in the art.
[0053] Reference to "about" a value or parameter herein includes
(and describes) variations that are directed to that value or
parameter per se. For example, a description referring to "about X"
includes the description of "X".
[0054] As used herein and in the appended claims, the singular
forms "a," "or," and "the" include plural referents unless the
context clearly dictates otherwise. It is understood that aspects
and variations of the subject matter described and disclosed herein
include "consisting" and/or "consisting essentially of" aspects and
variations.
[0055] Unless defined otherwise or clearly indicated by context,
all technical and scientific terms and abbreviations used herein
have the same meaning as commonly understood by one of ordinary
skill in the art to which this disclosure belongs.
DETAILED DESCRIPTION
[0056] Provided herein are novel methods of preparation of
1-(acyloxy)-alkyl carbamate prodrugs of amino containing drug
molecules.
[0057] In certain aspects, provided herein are novel methods of
preparation of 1-(acyloxy)-alkyl carbamate prodrugs of gabapentin
and related compounds.
[0058] In certain aspects, the present disclosure provides a method
of making a compound of formula (I), or a stereoisomer thereof, a
diastereomer thereof, or a salt of any one of foregoing,
comprising:
[0059] (A) reacting a compound of formula (II), or a stereoisomer
or a salt thereof, with R.sup.1CO.sub.2H to form a compound of
formula (III);
##STR00005##
and
[0060] (B) reacting the compound of formula (III), or a
stereoisomer or a salt thereof, with HNR.sup.4aR.sup.4b to form the
compound of formula (I):
##STR00006##
wherein:
[0061] each of R.sup.1 and R.sup.2 is independently C.sub.1-4
alkyl;
[0062] R.sup.3 is H or C.sub.1-4 alkyl;
[0063] HNR.sup.4aR.sup.4b is a drug molecule having an amino
moiety;
[0064] R.sup.4a and R.sup.4a are groups of the drug molecule
attached to the amino moiety;
[0065] each of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and R.sup.5e
is independently selected from a group consisting of H, halo,
C.sub.1-4 alkyl, halo C.sub.1-4 alkyl, phenyl, --C(O)O--C.sub.1-4
alkyl, --C(O)--C.sub.1-4 alkyl, --S(O)--C.sub.1-4 alkyl, CN,
--C(O)--NR.sup.6aR.sup.6b, substituted or unsubstituted C.sub.1-4
alkoxy, and substituted or unsubstituted phenoxy;
[0066] each of R.sup.6a and R.sup.6b is independently H, or
C.sub.1-4 alkyl; or R.sup.6a and R.sup.6b together with N they are
attached to form heterocycle;
[0067] provided that at least one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is other than H; or any two adjacent
R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and R.sup.5e are joined
together to form a carbocycle or heterocycle; and
[0068] X is a leaving group.
[0069] In some embodiments, the drug molecule HNR.sup.4aR.sup.4b is
a drug molecule containing a primary or a secondary amino
group.
[0070] In some embodiments, the drug molecule HNR.sup.4aR.sup.4b is
selected from acebutalol, albuterol, alprenolol, atenolol, bunolol,
bupropion, butopamine, butoxamine, carbuterol, cartelolol,
colterol, deterenol, dexpropanolol, diacetolol, dobutamine,
exaprolol, exprenolol, fenoterol, fenyripol, labotolol,
levobunolol, metolol, metaproterenol, metoprolol, nadolol,
pamatolol, penbutalol, pindolol, pirbuterol, practolol,
prenalterol, primidolol, prizidilol, procaterol, propanolol,
quinterenol, rimiterol, ritodrine, solotol, soterenol, sulfiniolol,
sulfinterol, sulictidil, tazaolol, terbutaline, timolol,
tiprenolol, tipridil, tolamolol, thiabendazole, albendazole,
albutoin, alendronate, alinidine, alizapride, amiloride, a minorex,
aprinocid, cambendazole, cimetidine, cisapride, clonidine,
cyclobenzadole, delavirdine, efegatrin, etintidine, fenbendazole,
fenmetazole, flubendazole, fludorex, gabapentin, icadronate,
lobendazole, mebendazole, metazoline, metoclopramide,
methylphenidate, mexiletine, neridronate, nocodazole, oxfendazole,
oxibendazole, oxmetidine, pamidronate, parbendazole, pramipexole,
prazosin, pregabalin, procainamide, ranitidine, tetrahydrazoline,
tiamenidine, tinazoline, tiotidine, tocamide, tolazoline,
tramazoline, xylometazoline, dimethoxyphenethylamine,
n-[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1-yl]acetyl-3(R)-methyl-.be-
ta.-alanine, adrenolone, aletamine, amidephrine, amphetamine,
aspartame, bamethan, betahistine, carbidopa, clorprenaline,
chlortermine, dopamine, L-dopa, ephrinephrine, etryptamine,
fenfluramine, methyldopamine, norepinephrine, enviroxime,
nifedipine, nimodipine, triamterene, pipedemic acid and similar
compounds,
1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-napthyridine-3-c-
arboxylic acid and
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazinyl)-3-quinolinecarbo-
xylic acid, theprubicin, deoxyspergualin, seglitide, nebracetam,
benanomicin B, eremomycin, thrazarine, tosufloxacin, baogongteng A,
angiopeptin, boholmycin, ravidomycin, tageflar, orienticins,
amphotericin B, tiamdipine, doxorubicin, lysobactin, mofegiline,
octreotide, oxolide, amikacin, phospholine, nuvanil, cispentacin,
chlorotetain, remacemide, ramoplanins, janthinomycins, mersacidin,
droxidopa, helvecardin A, helvecardin B, rilmazafone, vigabatrin,
amlodipine, (R)-(+)-amlodipine, mideplanin, milnacipran,
pranedipine, olradipine, deoxymethylspergualin, fudosteine,
trovafloxacin, ceranapril, restricticin, idarubicin, arbekacin,
giracodazole, poststatin, pazufloxacin, D-cycloserine, ovothiol A,
ceftizoxime, icatibant, p-iodorubidazone, aladapcin, dalargin,
seproxetine, pradimicin E, pradimicin FA-2, tafenoquine,
sampatrilat, ruboxyl, dactimicin, alatrofloxacin, galarubicin,
metaraminol, exatecan, squalamine, paromomycin, leustroducsin A,
leustroducsin B, leustroducsin C, lanicemine, azoxybacilin,
tetrafibricin, pixantrone, ziconotide, garomefrine, spinorphin,
doripenem, alestramustine, seraspenide, safingol, aminolevulinic
acid, pelagiomicin C, styloguanidine, L-4-oxalysine, eglumegad,
rhodopeptins, mycestericin E, midaxifylline, anisperimus, lagatide,
ibutamoren, oritavancin, ecenofloxacin, metyrosine, methyldopa,
baclofen, tranylcypromine, micronomicin, zorubicin, epirubicin,
gilatide, epithalon, cystamine, pluraflavin A, pluraflavin B,
pasireotide, caprazamycin, barusiban, spisulosine,
21-aminoepothilone B, capsavanil, olcegepant, sulphostin,
lobophorin A, papuamide A, papuamide B, cystocin, deoxynegamycin,
galnon, pyloricidin B, brasilicardin A, neramexane, kaitocephalin,
icofungipen, aliskiren, capromorelin, histaprodifen, donitriptan,
cambrescidins, tipifarnib, tabimorelin, belactosin A, belactosin C,
circinamide, targinine, sulphazocine, nepicastat, oseltamivir,
hydrostatin A, butabindide, netamiftide, memantine, fluvoxamine,
deferoxamine, tranexamic acid, fortimicin A, cefaclor, lisinopril,
ubestatin, cefminox, aspoxicillin, cefcanel, cefcanel daloxate,
olamufloxacin, R-(+)-aminoindane, gemifloxacin, kahalalide F,
palau'amine, examorelin, leustroducsin H, sabarubicin, amifostine,
L-homothiocitrulline, L-thiocitrulline, impentamine, neboglamine,
amselamine, cetefloxacin, cyclothialidine, fluvirucin B2,
loracarbef, cefprozil, sperabillins, milacamide, avizafone,
.alpha.-methyltryptophan, cytaramycin, lanomycin, decaplanin,
eflornithine, L-histidinol, tuftsin, kanamycin, amthamine,
sitafloxacin, leurubicin, amantadine, isodoxorubicin, gludopa,
bactobolin, esafloxacin, tabilautide, lazabemide, enalkiren,
amrubicin, daunorubicin, mureidomycins, pyridazomycin, cimaterol,
(+)-isamoltan, N-desmethylmilameline, noberastine, fosopamine,
adaprolol, pradimicin B, amosulalol, xamoterol, boholmycin,
risotilide, indeloxazine, denopamine, parodilol, utibapril,
nardeterol, biemnidin, sparfloxacin, sibanomicin, tianeptine,
oberadilol, methoctramine, sezolamide, anabasine, zilpaterol,
zabiciprilat, enkastins, ulifloxacin, (+)-sotalol,
deoxynojirimycin, altromycin A, altromycin C, dorzolamide,
fepradinol, delapril, ciprofloxacin, balofloxacin, mepindolol,
berlafenone, ramipril, dopexamine, dilevalol, (-)-nebivolol,
duramycin, enalapril, meluadrine, zelandopam, voglibose,
sertraline, carvedilol, pafenolol, paroxetine, fluoxetine,
phendioxan, salmeterol, solpecainol, repinotan, bambuterol,
safinamide, tilisolol, 7-oxostaurosporine, caldaret, sertraline,
cilazapril, benazepril, prisotinol, gatifloxacin, ovothiol B,
adaprolol, tienoxolol, fluparoxan, alprenoxime, efegatran,
pradimicin, salbostatin, ersentilide, (S)-noremopamil, esperamicin
A1, batoprazine, ersentilide, osutidine, quinapril, dihydrexidine,
argiopine, pradimicin D, frovatriptan, hispidospermidin, silodosin,
michellamine B, sibenadet, tetrindol, talibegron, topixantrone,
nortopixantrone, tecalcet, buteranol, .alpha.-methylepinephrine,
nornicotine, thiofedrine, lenapenem, imidapril, epibatidine,
premafloxacin, socorromycin, trandolapril, tamsulosin,
dirithromycin, inogatran, vicenistatin, immepyr, immepip, balanol,
orbifloxacin, maropitant, dabelotine, lerisetron, ertapenem,
nolomirole, moxifloxacin, vofopitant, halofuginone, melagatran,
ximelagatran, fasudil, isofagomine, pseudoephedrine, propafenone,
celiprolol, carteolol, penbutolol, labetalol, acebutolol,
reproterol, rimoterol, amoxapine, maprotiline, viloxazine,
protriptyline, nortriptyline, desipramine, oxprenolol, propranolol,
ketamine, butofilolol, flecamide, tulobuterol, befunolol,
immucillin-H, vestipitant, cinacalcet, lapatinib, desloratadine,
ladostigil, vildagliptin, tulathromycin B, becampanel, salbutamol,
delucemine, solabegron, paroxetine, gaboxadol, telavancin,
ralfinamide, tomoxetine, dalbavancin, elarofiban, ferulinolol,
fenoldopam, sumanirole, sarizotan, brinzolamide, pradofloxacin,
garenoxacin, reboxetine, ezlopitant, palindore, nebivolol,
dinapsoline, proxodolol, repinotan, demexiptiline, mitoxantrone,
norfloxacin, dilevalol, nipradilol, esmolol, ibopamine, troxipide,
arotinolol, formoterol, bopindolol, cloranolol, mefloquine,
perindopril, mabuterol, bisoprolol, bevantolol, betaxolol,
tertatolol, enoxacin, lotrafiban, moexipril, droxinavir,
adrogolide, alniditan, tigecycline, lubazodone, meropenem,
temocapril, napsamycins, (-)-cicloprolol, ecteinascidins,
alprafenone, landiolol, tirofiban, noberastine, rasagiline,
setazindol, picumeterol, arbutamine, mecamylamine, delfaprazine,
imidapril, midafotel, manzamines, binospirone, duloxetine, and
litoxetine.
[0071] In some embodiments, the drug molecule is any secondary or
primary amine drug HNR.sup.4aR.sup.4b described in various
compendia accessible to the skilled artisan, such as, for example,
the Merck Index, 13.sup.th Edition, 2001 or the Physicians Desk
Reference, 59.sup.th Edition, 2005. Accordingly, secondary or
primary amine drugs HNR.sup.4aR.sup.4b described in references such
as those, supra, are within the ambit of the present
description.
[0072] In some embodiments, the drug molecule is selected from
alendronate, amifostine, rac-baclofen, R-baclofen, carbidopa,
clonidine, ciprofloxacin, cisapride, daunorubicin, doxorubicin,
fenoldopam, fenoterol, gabapentin, gentamycin, kanamycin, levodopa,
meropenem, metazoline, neomycin, pamidronate, pregabalin,
tobramycin, trovafloxacin and vigabatrin. In yet other embodiments,
the drug molecule HNR.sup.4aR.sup.4b is gabapentin. In still other
embodiments, HNR.sup.4aR.sup.4b is R-baclofen. In still other
embodiments, HNR.sup.4aR.sup.4b is a GABA analog.
[0073] In some embodiments, X is halo.
[0074] In some embodiments, X is Cl.
[0075] In some embodiments, the reaction step (A) occurs in a
solvent.
[0076] In another embodiment, the reaction step (A) occurs in
absence of any solvent.
[0077] In yet another embodiment, the reaction step (A) occurs in
an aprotic solvent.
[0078] In yet another embodiment, the reaction step (A) occurs in a
protic solvent.
[0079] In yet another embodiment, the reaction step (A) occurs in a
solvent selected from heptane, xylene, toluene,
N-methylpyrrolidine, N,N-diisopropylamine, dimethyl formamide,
dimethyl sulfoxide, diphenyl ether, and combinations thereof. In
some embodiments, the reaction step (A) occurs in heptane, xylene,
toluene, or N-methylpyrrolidine. In some embodiments, the reaction
step (A) occurs in xylene or heptane. In some embodiments, the
reaction step (A) occurs in heptane. In certain embodiments,
hepatane is a mixture of heptanes.
[0080] In yet another embodiment, the reaction step (A) occurs in a
solvent which is inert to the carboxylic acid salt. In one
embodiment, the solvent is alcohol (such as methanol, ethanol,
isopropanol, or tert-butanol), water, dichloromethane,
dichloroethane, dimethylformamide, dimethylacetamide,
hexamethylphosphoramide, N-methylpyrrolidinone, dimethyl sulfoxide,
pyridine, ethyl acetate, acetone, 2-butanone, methyl-tert-butyl
ether, chloroform, acetonitrile, benzene, toluene, xylene or a
carboxylic acid (such as the corresponding carboxylic acid), or
mixtures thereof. In some embodiments, the reaction takes place at
a suitable temperature such as from room temperature to the boiling
point of the particular solvent or solvent combination
employed.
[0081] In some embodiments, the reaction step (A) occurs at a
temperature from about 50.degree. C. to about 120.degree. C. In
some embodiments, the reaction step (A) occurs at a temperature
from about 90.degree. C. to about 120.degree. C. In some
embodiments, the reaction step (A) occurs at a temperature from
about 115.degree. C. to about 120.degree. C.
[0082] In some embodiments, the reaction step (A) occurs by
reaction of a metal salt of R.sup.1CO.sub.2H with the compound of
formula (II). The cation of the salt can be silver, copper,
mercury, sodium, potassium, lithium, caesium, calcium, magnesium or
zinc. In certain embodiments, the molar ratio of the carboxylic
acid salt to the compound for formula (II) or salt thereof is
between 1:1 and 1:20, more particularly between 1:1 and 1:5 and
most particularly about 1:1.
[0083] In some embodiments, the reaction step (A) occurs in the
presence of a metal oxide.
[0084] In some embodiments, the reaction step (A) occurs in the
presence of a metal oxide; and the metal is silver, copper,
mercury, sodium, potassium, lithium, caesium, calcium, magnesium or
zinc. In certain embodiments, the reaction step (A) occurs in the
presence of Cu.sub.2O. In some embodiments, with respect to the
reaction in the presence of Cu.sub.2O, the corresponding carboxylic
acid, a mixture of heptane or o-xylene and the corresponding
carboxylic acid, a mixture of xylene isomers and ethylbenzene (all
contained in the solvent mixture designated "xylenes") or toluene
may be used as a solvent.
[0085] In some embodiments, the reaction step (A) occurs in the
presence of a metal alkanoate; or a metal salt of R.sup.1CO.sub.2H;
and R.sup.1 is as defined herein. In certain embodiments, the metal
is silver, copper, mercury, sodium, potassium, lithium, cesium,
calcium, magnesium or zinc. In some embodiments, the reaction step
(A) occurs in the presence of a silver salt of
R.sup.1CO.sub.2H.
[0086] In some embodiments, the reaction step (A) occurs in the
presence of silver isobutyrate. In certain embodiments, when the
reaction step (A) occurs in the presence of silver isobutyrate, the
reaction takes place at a suitable temperature, such as 90.degree.
C. In certain embodiments, for this step, the corresponding
carboxylic acid may be used as a solvent. For example, when R.sup.1
is isopropyl, isobutyric acid may be used as a solvent.
[0087] In some embodiments, the reaction step (A) occurs in the
presence of R.sup.1C(O)--O--C(O)R.sup.1; and R.sup.1 is as defined
herein. In certain embodiments, the reaction step (A) occurs in the
presence of isobutyric anhydride.
[0088] In some embodiments, the reaction step (A) occurs in the
presence of an organic base, such as N,N-diisopropylethylamine,
triethylamine, tributylamine, dimethylisopropylamine,
N-methylmorpholine, N-methypyrrolidine, N-methylpiperidine,
pyridine, 2-methylpyridine, 2,6-methylpyridine,
4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane,
1,8-diazabicyclo[5.4.0]undec-7-ene or
1,1-diazabicyclo[4.3.0]undec-7-ene or by reaction with a quaternary
ammonium salt of the corresponding carboxylic acid, wherein the
cation is tetramethylammonium, tetraethylammonium or
tetrabutylammonium. In certain embodiments, the molar ratio of the
carboxylic acid or the quaternary ammonium salt of the carboxylic
acid to the compound of formula (II) or salt thereof is between 1:1
and 1:20, more particularly between 1:1 and 1:5 and most
particularly about 1:1. The reaction is typically conducted in a
solvent which is inert to the carboxylic acid or quaternary
ammonium salt of the carboxylic acid such as alcohol (such as
methanol, ethanol, isopropanol, or tert-butanol), water,
dichloromethane, dichloroethane, dimethylformamide,
dimethylacetamide, hexamethylphosphoramide, N-methylpyrrolidinone,
dimethyl sulfoxide, pyridine, ethyl acetate, acetone, 2-butanone,
methyl-tert-butyl ether, chloroform, acetonitrile, benzene,
toluene, xylene or a carboxylic acid (such as the corresponding
carboxylic acid), or mixtures thereof. The reaction takes place at
a suitable temperature such as from room temperature to the boiling
point of the particular solvent or solvent combination employed. In
some embodiments, the organic base is N,N-diisopropylethylamine. In
certain embodiments of this step, a catalytic amount of an iodide
or bromide salt (e.g. sodium iodide, potassium iodide,
tetramethylammonium iodide or tetrabutylammonium iodide or
n-tetrabutylammonium bromide, particularly sodium iodide) may be
used. The reaction takes place at a suitable temperature, such as
80.degree. C. A mixture of dimethyl carbonate and the isobutyric
acid may be used as a solvent.
[0089] In some embodiments, the reaction step (A) occurs in the
presence of a tetraalkylammonium salt. In certain embodiments, the
reaction step (A) occurs in the presence of tetraalkylammonium
chloride, tetraalkylammonium bromide, or tetraalkylammonium iodide.
In some embodiments, the reaction step (A) occurs in the presence
of tetrabutylammonium bromide.
[0090] In some embodiments, the reaction step (A) occurs over a
period of 0.5 to 10 hr. In some embodiments, the reaction occurs
over a period of 1-7 hrs. In some embodiments, the reaction occurs
over a period of 3-5 hrs.
[0091] In some embodiments, when R.sup.3 is H, the reaction step
(A) may further comprise preparation of individual stereoisomers or
pure enantiomers of the compound of formula (III).
[0092] In some embodiments, when R.sup.3 is H, the reaction step
(A) may further comprise enzymatic resolution of the compound of
formula (III). In certain embodiments, the enzymatic resolution
occurs in the presence of a suitable enzyme. In some embodiments,
the enzyme is an esterase enzyme. In some embodiments, the enzyme
is lipase. In some embodiments, the resolution occurs in the
presence of a phosphate buffer.
[0093] In some embodiments, the enzymatic resolution is carried out
by following procedures as described in U.S. Pat. No. 7,872,046 or
8,062,870.
[0094] In some embodiments, the enzymatic resolution is used to
prepare the compounds according to formulae (III-A) and
(III-B):
##STR00007##
wherein R.sup.1 and R.sup.5a-R.sup.5e are as defined herein.
[0095] In some embodiments, the reaction step (B) occurs in a
protic or aprotic solvent; or combinations thereof.
[0096] In some embodiments, the reaction step (B) occurs in an
alcohol solvent. In some embodiments, the reaction step (B) occurs
in a combination of alcohol solvents. In certain embodiments, the
alcohol solvent is methanol, ethanol, i-propanol, or n-propanol. In
some embodiments, the alcohol solvent is i-propanol or
isopropanol.
[0097] In another embodiment, the reaction step (B) occurs in
heptane, xylene, toluene, dialkyl ether, cyclic ethers, dimethyl
formamide, dimethyl sulfoxide, water, acetonitrile, ethyl acetate,
or combinations thereof.
[0098] In some embodiments, the reaction step (B) occurs in t-butyl
methyl ether, heptane, THF, water, acetonitrile, or combinations
thereof.
[0099] In some embodiments, the reaction step (B) occurs in a
mixture of heptane, water, and acetonitrile.
[0100] In some embodiments, the reaction step (B) occurs in a
mixture of t-butyl methyl ether, water, and acetonitrile.
[0101] In certain embodiments, the reaction step (B) occurs at a
temperature from about 0.degree. C. to about 80.degree. C., about
10.degree. C. to about 60.degree. C. or about 10.degree. C. to
about 50.degree. C. In some embodiments, the reaction step (B)
occurs at a temperature from about 10.degree. C. to about
20.degree. C.
[0102] In some embodiments, the reaction step (B) occurs in the
presence of a base. In some embodiments, the base is an inorganic
base. In other embodiments, the base is an organic base.
[0103] In some embodiments, the reaction step (B) occurs in the
presence of triethylamine, tetramethylguanidine (TMG), aqueous
NaOH, aqueous KOH, aqueous Na.sub.2CO.sub.3, aqueous
K.sub.2CO.sub.3, aqueous NaHCO.sub.3, aqueous KHCO.sub.3, or
mixtures thereof.
[0104] In some embodiments, R.sup.1 is methyl, ethyl, isopropyl, or
n-propyl.
[0105] In some embodiments, R.sup.1 is isopropyl.
[0106] In some embodiments, R.sup.2 is methyl, ethyl, isopropyl or
n-propyl.
[0107] In some embodiments, R.sup.2 is methyl or isopropyl.
[0108] In some embodiments, R.sup.3 is hydrogen.
[0109] In some embodiments, one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is selected from halo, C.sub.1-4 alkyl,
--C(O)O--C.sub.1-4 alkyl, --C(O)--C.sub.1-4 alkyl,
--S(O)--C.sub.1-4 alkyl, CN, --C(O)--NR.sup.6aR.sup.6b, or
substituted or unsubstituted alkoxy, and the rest are H. In other
embodiments, two of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and
R.sup.5e are independently selected from halo, C.sub.1-4 alkyl,
--C(O)O--C.sub.1-4 alkyl, --C(O)--C.sub.1-4 alkyl,
--S(O)--C.sub.1-4 alkyl, CN, --C(O)--NR.sup.6aR.sup.6b, or
substituted or unsubstituted alkoxy, and the rest are H. In other
embodiments, three of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and
R.sup.5e are independently selected from halo, C.sub.1-4 alkyl,
--C(O)O--C.sub.1-4 alkyl, or substituted or unsubstituted alkoxy,
and the rest are H.
[0110] In some embodiments, one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is --C(O)--NR.sup.6aR.sup.6b; and each of
R.sup.6a and R.sup.6b is independently H or C.sub.1-4 alkyl. In
other embodiments, one of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d,
and R.sup.5e is --C(O)--NR.sup.6aR.sup.6b; and R.sup.6a and
R.sup.6b together with N they are attached to form a heterocycle.
In some embodiments, one of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d,
and R.sup.5e is --C(O)--NH.sub.2, or --C(O)NMe.sub.2. In other
embodiments, R.sup.5c is --C(O)--NH.sub.2, or --C(O)NMe.sub.2.
[0111] In some embodiments, one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is --C(O)--C.sub.1-4 alkyl. In other
embodiments, one of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and
R.sup.5e is --C(O)Me, or --C(O)Et. In some embodiments, R.sup.5c is
--C(O)Me, or --C(O)Et.
[0112] In some embodiments, one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is --S(O)--C.sub.1-4 alkyl. In other
embodiments, one of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and
R.sup.5e is --S(O)Me, or --S(O)Et. In some embodiments, R.sup.5c is
--S(O)Me, or --S(O)Et.
[0113] In some embodiments, one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is CN. In some embodiments, R.sup.5c is
CN.
[0114] In some embodiments, R.sup.5a is halo. In other embodiments,
R.sup.5a is F, or Cl.
[0115] In some embodiments, R.sup.5a is F; and each of R.sup.5b,
R.sup.5c, R.sup.5d, and R.sup.5e is H.
[0116] In other embodiments, one, two, three, or four of
R.sup.5aR.sup.5b, R.sup.5c, R.sup.5d, and R.sup.5e is/are
independently Cl, F, Me, Et, --C(O)OMe or --C(O)OEt; and the rest
are H.
[0117] In some embodiments, R.sup.5c is --C(O)OMe or Me; and each
of R.sup.5a, R.sup.5b, R.sup.5d, and R.sup.5e is H.
[0118] In some embodiments, R.sup.5c is --C(O)Me; and each of
R.sup.5a, R.sup.5b, R.sup.5d, and R.sup.5e is H.
[0119] In some embodiments, R.sup.5c is --S(O)OMe or Me; and each
of R.sup.5a, R.sup.5b, R.sup.5d, and R.sup.5e is H.
[0120] In some embodiments, R.sup.5c is --S(O)Me; and each of
R.sup.5a, R.sup.5b, R.sup.5d, and R.sup.5e is H.
[0121] In some embodiments, R.sup.5c is --C(O)--NH.sub.2, or
--C(O)NMe.sub.2; and each of R.sup.5a, R.sup.5b, R.sup.5d, and
R.sup.5e is H.
[0122] In some embodiments, R.sup.5c is CN; and each of R.sup.5a,
R.sup.5b, R.sup.5d, and R.sup.5e is H.
[0123] In other embodiments, R.sup.5b is --OMe; and each of
R.sup.5a, R.sup.5e, R.sup.5d, and R.sup.5e is H.
[0124] In other embodiments, any two of R.sup.5a, R.sup.5b,
R.sup.5c, R.sup.5d, and R.sup.5e form --O--CH.sub.2--O--, or
--O--CH.sub.2--CH.sub.2--O--; and the rest are H.
[0125] In other embodiments, each of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, or R.sup.5e is independently selected from H, halo,
C.sub.1-4 alkyl, halo C.sub.1-4 alkyl, phenyl, --C(O)O--C.sub.1-4
alkyl, --C(O)--C.sub.1-4 alkyl, --S(O)--C.sub.1-4 alkyl, CN,
--C(O)--NR.sup.6aR.sup.6b, substituted or unsubstituted C.sub.1-4
alkoxy, and substituted or unsubstituted phenoxy; and provided that
the pKa of the starting phenol (II') is about 7-11.
##STR00008##
[0126] In other embodiments, the pKa is about 8 to 10. In some
embodiments, the pKa is about 8 to 9. In other embodiments, the pKa
is about 8.1 to 8.5. In some embodiments, the pKa is about 8, 8.1,
8.2, 8.3, 8.4, or 8.5.
[0127] In some embodiments, when R.sup.5a is fluoro and R.sup.5b,
R.sup.5c, R.sup.5d and R.sup.5e are hydrogen, the step (B) takes
place in the presence of a base such as aqueous sodium hydroxide in
a solvent such as tetrahydrofuran. In other embodiments,
triethylamine base could be used and a mixture of water,
acetonitrile and heptanes could be used as the solvent. In some
embodiments, the reaction takes place at a temperature from
10.degree. C. to 30.degree. C.
[0128] In some embodiments, when R.sup.5a is chloro and R.sup.5b,
R.sup.5c, R.sup.5d and R.sup.5e are hydrogen, the step (B) takes
place in the presence of a base such as aqueous sodium hydroxide in
a solvent such as tetrahydrofuran, and at a temperature from
0.degree. C. to 50.degree. C.
[0129] In other embodiments, R.sup.5b is halo and R.sup.5a,
R.sup.5c, R.sup.5d and R.sup.5e are hydrogen. In some embodiments,
R.sup.5b is fluoro and R.sup.5a, R.sup.5c, R.sup.5d and R.sup.5e
are hydrogen.
[0130] In some embodiments, when R.sup.5b is fluoro and R.sup.5a,
R.sup.5c, R.sup.5d and R.sup.5e are hydrogen, the step (B) takes
place in the presence of a base such as triethylamine in a solvent
such as a mixture of water, acetonitrile and tert-butyl methyl
ether, and at a temperature from 10.degree. C. to 20.degree. C.
[0131] In some embodiments, R.sup.5c is halo and R.sup.5a,
R.sup.5b, R.sup.5d and R.sup.5e are hydrogen. In some embodiments,
R.sup.5c is fluoro and R.sup.5a, R.sup.5b, R.sup.5d and R.sup.5e
are hydrogen.
[0132] In some embodiments, when R.sup.5c is fluoro and R.sup.5a,
R.sup.5b, R.sup.5d and R.sup.5e are hydrogen, the step (B) takes
place in the presence of a base such as triethylamine in a solvent
such as a mixture of water, acetonitrile and tert-butyl methyl
ether, and at a temperature from 0.degree. C. to 20.degree. C.
[0133] In some embodiments, two of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d and R.sup.5e are halo and the remaining groups are
hydrogen. In some embodiments, two of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d and R.sup.5e are fluoro and the remaining groups are
hydrogen. In some embodiments, R.sup.5a and R.sup.5e are fluoro and
R.sup.5b, R.sup.5c and R.sup.5d are hydrogen.
[0134] In some embodiments, when R.sup.5a and R.sup.5e are fluoro
and R.sup.5b, R.sup.5c and R.sup.5d are hydrogen, the step (B)
takes place in a solvent such as a mixture of water and
acetonitrile, at a temperature from 10.degree. C. to 60.degree.
C.
[0135] In some embodiments, one or more of R.sup.5a, R.sup.5b,
R.sup.5c, R.sup.5d and R.sup.5e is --OC.sub.1-3 alkyl and the
remaining groups are hydrogen. In some embodiments, one of
R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d and R.sup.5e is methoxy and
the remaining groups are hydrogen.
[0136] In some embodiments, R.sup.5b is --OC.sub.1-3alkyl and
R.sup.5a, R.sup.5c, R.sup.5d and R.sup.5e are hydrogen. In some
embodiments, R.sup.5b is methoxy and R.sup.5a, R.sup.5c, R.sup.5d
and R.sup.5e are hydrogen.
[0137] In some embodiments, when R.sup.5b is methoxy and R.sup.5a,
R.sup.5c, R.sup.5d and R.sup.5e are hydrogen, the step (B) takes
place in the presence of a base such as aqueous sodium hydroxide
and tetramethylguanidine in a solvent such as a tetrahydrofuran, at
a temperature of 20.degree. C.
[0138] In some embodiments, R.sup.4a is H.
[0139] In some embodiments, R.sup.4b is
##STR00009##
and wherein the * represents the attachment point.
[0140] In other embodiments, R.sup.4b is
##STR00010##
and wherein the * represents the attachment point.
[0141] In other embodiments, R.sup.4b is
##STR00011##
wherein the * represents the attachment point; and R.sup.7 is F or
Cl.
[0142] In some embodiments, R.sup.7 is F. In other embodiments,
R.sup.7 is Cl.
[0143] In some embodiments, R.sup.4b is
##STR00012##
wherein the * represents the attachment point.
[0144] In some embodiments, with respect to the compound of formula
(I), the compound is a compound according to formula (IVa), (IVb),
(IVc), or (IVd):
##STR00013##
or a salt thereof.
[0145] In some embodiments, with respect to the compound of formula
(I), the compound is a compound according to formula (IVe):
##STR00014##
or a salt thereof.
[0146] In another aspect, the process of the present disclosure is
for the preparation of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid or a salt thereof. In some embodiments, the product of
the process of the present disclosure is
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid. In some embodiments, the process of the present
disclosure is for the preparation of crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid. Crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid may be prepared from
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid as described in PCT Publication No. WO 2005/037784, the
contents of which are incorporated herein by reference. In some
embodiments, crystallisation is induced by seeding a solution of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid with crystals of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid.
[0147] In another aspect, the present disclosure provides a
compound according to formula (III):
##STR00015##
or a stereoisomer thereof, a diastereomer thereof; or a salt of any
one of foregoing; wherein each R.sup.1 and R.sup.2 is independently
C.sub.1-4 alkyl; R.sup.3 is H or C.sub.1-4 alkyl; and each of
R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, or R.sup.5e is
independently selected from H, halo, C.sub.1-4 alkyl, halo
C.sub.1-4 alkyl, phenyl, --C(O)O--C.sub.1-4 alkyl,
--C(O)--C.sub.1-4 alkyl, --S(O)--C.sub.1-4 alkyl, CN,
--C(O)--NR.sup.6aR.sup.6b, substituted or unsubstituted C.sub.1-4
alkoxy, and substituted or unsubstituted phenoxy; each R.sup.6a and
R.sup.6b is independently H, or C.sub.1-4 alkyl; or R.sup.6a and
R.sup.6b together with the N they are attached to form heterocycle;
provided that at least one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is other than H; or any two of R.sup.5a,
R.sup.5b, R.sup.5c, R.sup.5d, and R.sup.5e form --O--CH.sub.2--O--,
or --O--CH.sub.2--CH.sub.2--O--.
[0148] In some embodiments, R.sup.1 is Me, Et, n-Pr, i-Pr, n-Bu,
i-Bu, sec-Bu, or t-Bu.
[0149] In some embodiments, R.sup.1 is i-Pr.
[0150] In some embodiments, R.sup.3 is H, Me, Et, n-Pr, i-Pr, n-Bu,
i-Bu, sec-Bu, or t-Bu.
[0151] In some embodiments, R.sup.3 is H.
[0152] In some embodiments, with respect to the compound of formula
(III), the compound is a compound according to formula (V):
##STR00016##
or a stereoisomer thereof, a diastereomer thereof; or a salt of any
one of foregoing; and wherein R.sup.2, R.sup.5a, R.sup.5b,
R.sup.5c, R.sup.5d, and R.sup.5e are as defined herein.
[0153] In some embodiments, with respect to the compound of formula
(III) or (V), R.sup.2 is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, sec-Bu, or
t-Bu. In some embodiments, R.sup.2 is Me or i-Pr.
[0154] In some embodiments, with respect to the compound of formula
(III), the compound is a compound according to formula (VIa) or
(VIb):
##STR00017##
or a stereoisomer thereof, a diastereomer thereof; or a salt of any
one of foregoing; wherein R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d,
and R.sup.5e are as defined herein.
[0155] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is halo, C.sub.1-4 alkyl, --C(O)O--C.sub.1-4
alkyl, or substituted or unsubstituted alkoxy, and the rest are H.
In other embodiments, two of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e are independently halo, C.sub.1-4 alkyl,
--C(O)O--C.sub.1-4 alkyl, --C(O)--C.sub.1-4 alkyl,
--S(O)--C.sub.1-4 alkyl, CN, --C(O)--NR.sup.6aR.sup.6b, or
substituted or unsubstituted alkoxy, and the rest are H. In other
embodiments, three of R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and
R.sup.5e are independently halo, C.sub.1-4 alkyl,
--C(O)O--C.sub.1-4 alkyl, or substituted or unsubstituted alkoxy,
and the rest are H.
[0156] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5a is halo. In other embodiments,
R.sup.5a is F, or Cl.
[0157] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5a is F; and each of R.sup.5b,
R.sup.5c, R.sup.5d, and R.sup.5e is H.
[0158] In other embodiments, with respect to the compound of
formula (III), (V), (VIa) or (VIb), one, two, three, or four of
R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and R.sup.5e is/are
independently Cl, F, Me, Et, --C(O)OMe, --C(O)OEt, --COMe, --SOMe,
--CONH.sub.2, CONMe.sub.2, or --CN; and the rest are H.
[0159] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5c is --C(O)OMe or Me; and each
of R.sup.5a, R.sup.5b, R.sup.5d, and R.sup.5e is H.
[0160] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5c is --C(O)Me or --S(O)Me; and
each of R.sup.5a, R.sup.5b, R.sup.5d, and R.sup.5e is H.
[0161] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5c is --C(O)--NH.sub.2, or
--C(O)NMe.sub.2; and each of R.sup.5a, R.sup.5b, R.sup.5d, and
R.sup.5e is H.
[0162] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5c is CN; and each of R.sup.5a,
R.sup.5b, R.sup.5d, and R.sup.5e is H.
[0163] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5b is --OMe; and each of
R.sup.5a, R.sup.5e, R.sup.5d, and R.sup.5e is H.
[0164] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is halo, and the rest are H.
[0165] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), two of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e are halo, and the rest are H.
[0166] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), three of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e are halo, and the rest are H.
[0167] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5a, R.sup.5b, or R.sup.5e is Cl
or F.
[0168] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5a is Cl or F.
[0169] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5b is Cl or F.
[0170] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5c is Cl or F.
[0171] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), each of R.sup.5a and R.sup.5e is Cl or
F.
[0172] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is independently Cl, F, Me, Et, C(O)OMe or
C(O)OEt, and the rest are H.
[0173] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5c is C(O)OMe or Me.
[0174] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), one of R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, and R.sup.5e is OMe, and the rest are H.
[0175] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5c is OMe.
[0176] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), one or two of R.sup.5a, R.sup.5b,
R.sup.5c, R.sup.5d, and R.sup.5e is/are CF.sub.3, and the rest are
H.
[0177] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5a is --CF.sub.3. In other
embodiments, R.sup.5e is CF.sub.3.
[0178] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), any two of R.sup.5a, R.sup.5b,
R.sup.5c, R.sup.5d, and R.sup.5e form O--CH.sub.2--O--, or
O--CH.sub.2--CH.sub.2--O--.
[0179] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5a and R.sup.5b form
O--CH.sub.2--O--.
[0180] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5b and R.sup.5e form
O--CH.sub.2--O--.
[0181] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5a and R.sup.5b form
O--CH.sub.2--CH.sub.2--O--.
[0182] In some embodiments, with respect to the compound of formula
(III), (V), (VIa) or (VIb), R.sup.5b and R.sup.5e form
O--CH.sub.2--CH.sub.2--O--.
[0183] In some embodiments, with respect to the compound of formula
(III), the compound is a compound according to formula (VIIa),
(VIIb), (VIIc), (VIId), (VIIe), (VIIf), (VIIg), or (VIIh):
##STR00018##
or a stereoisomer thereof, a diastereomer thereof; or a salt of any
one of foregoing.
[0184] In some embodiments, with respect to the compound of formula
(III), the compound is a compound according to formula (VIIIa),
(VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf):
##STR00019##
or a stereoisomer thereof, a diastereomer thereof; or a salt of any
one of foregoing.
[0185] In some embodiments, with respect to the compound of formula
(III), the compound is a compound according to formula (IXa),
(IXb), (IXc), (IXd), (IXe), (IXf), (IXg), or (IXh):
##STR00020##
or a stereoisomer thereof, a diastereomer thereof; or a salt of any
one of foregoing.
[0186] In some embodiments, with respect to the compound of formula
(III), the compound is a compound according to formula (Xa), (Xb),
(Xc), (Xd), (Xe), or (Xf):
##STR00021##
or a stereoisomer thereof, a diastereomer thereof; or a salt of any
one of foregoing.
[0187] In some embodiments, with respect to the compound of formula
(III), the compound is a compound according to formula (XIa),
(XIb), (XIc), (XId), (XIe), (XIf), (XIg), or (XIh):
##STR00022##
a stereoisomer thereof, a diastereomer thereof; or a salt
thereof.
[0188] In some embodiments, with respect to the compound of formula
(III), the compound is a compound according to formula (XIIa),
(XIIb), (XIIc), (XIId), (XIIe), or (XIIf):
##STR00023##
a stereoisomer thereof, a diastereomer thereof; or a salt
thereof.
[0189] In some embodiments, with respect to the compound of formula
(III), the compound is a compound according to formula (XIIIa),
(XIIIb), (XIIIc), (XIIId), (XIIIe), (XIIIf), (XIIIg), or
(XIIIh):
##STR00024##
a stereoisomer thereof, a diastereomer thereof; or a salt
thereof.
[0190] In some embodiments, with respect to the compound of formula
(III), the compound is a compound according to formula (XIVa),
(XIVb), (XIVc), (XIVd), (XIVe), or (XIVf):
##STR00025##
a stereoisomer thereof, a diastereomer thereof; or a salt
thereof.
[0191] In some embodiments, with respect to the compound of formula
(III), the compound is a compound according to formula (XVa),
(XVb), (XVc), (XVd), (XVe), or (XVf):
##STR00026##
a stereoisomer thereof, a diastereomer thereof; or a salt
thereof.
[0192] In some embodiments, with respect to the compound of formula
(III), the compound is a compound according to formula (XVIa),
(XVIb), (XVIc), (XVId), (XVIe), or (XVIf):
##STR00027##
[0193] a stereoisomer thereof, a diastereomer thereof; or a salt
thereof.
[0194] In some embodiments, with respect to the compound of formula
(III), the compound may form solvates (e.g. hydrates).
[0195] Certain compounds and salts used in the process of the
present disclosure may form solvates (e.g. hydrates).
[0196] In the context of this disclosure, reference to a salt of a
compound encompasses all possible stoichiometric and
non-stoichiometric forms of that salt. Because of their potential
use in medicine, in some embodiments, the salts of the compound of
formula (I) are pharmaceutically acceptable.
[0197] Pharmaceutically acceptable base addition salts of compounds
of formula (I) include metal salts (such as sodium, potassium,
aluminum, calcium, magnesium and zinc) and ammonium salts (such as
isopropylamine, diethylamine, and diethanolamine salts). Such salts
may be prepared by the skilled chemist, by treating a compound of
formula (I) with the appropriate base in a suitable solvent,
followed by crystallisation and filtration.
[0198] Certain compounds used in the process of the present
disclosure are capable of existing in stereoisomeric forms. It will
be understood that reference to these compounds encompasses all
geometric and optical isomers of these compounds and the mixtures
thereof including racemates. The present disclosure also extends to
any tautomeric forms and mixtures thereof.
[0199] Certain processes of the present disclosure are beneficially
conducted as continuous processes. Additionally, the mass
efficiency (calculated by dividing the mass of product by the mass
of starting materials) of certain processes of the present
disclosure is high (higher mass efficiencies are more
environmentally friendly). Specifically, where the compound of
formula (III) is 2-chlorophenol, mass efficiencies of 2.0% without
solvent recovery, or 3.0% with solvent recovery can be achieved. In
combination with the cost of starting materials, these features
combine to make processes of the present disclosure commercially
attractive.
[0200] In another aspect, the present disclosure provides a
compound of formula (I) or a salt thereof obtainable by the
processes of the present disclosure. The present disclosure also
provides a pharmaceutical composition which comprises a compound of
formula (I) obtained by the processes of the present disclosure, or
a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier. The present disclosure also provides a compound
of formula (I), or a pharmaceutically acceptable salt thereof,
obtained by the processes of the present disclosure for use as a
therapeutic substance in the treatment of epilepsy, pain
(particularly neuropathic pain such as post-herpetic neuralgia or
diabetic painful neuropathy, or pain associated with irritable
bowel syndrome), anxiety (particularly general anxiety disorder),
alcohol dependency (ethanol withdrawal syndrome), restless legs
syndrome, migraine prophylaxis, fibromyalgia, hot flashes
(particularly hot flashes associated with the menopause) and
essential tremor.
[0201] In some embodiments, the compound of formula (III) is
selected from: [0202] 1-({[(2-Fluorophenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate; [0203]
1-({[(3-Fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate;
[0204] 1-({[(4-Fluorophenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate; [0205]
1-({[(2,6-Difluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate;
[0206] 1-({[(2-Chlorophenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate; and [0207]
1-[({[3-(Methyloxy)phenyl]oxy}carbonyl)oxy]ethyl
2-methylpropanoate.
[0208] Additional embodiments within the scope provided herein are
set forth in non-limiting fashion elsewhere herein and in the
examples. It should be understood that these examples are for
illustrative purposes only and are not to be construed as limiting
in any manner.
GENERAL SYNTHETIC PROCEDURES
[0209] The compounds, intermediates and starting materials provided
herein can be purchased or prepared from readily available starting
materials using general methods and procedures. See, e.g.,
Synthetic Schemes below. It will be appreciated that where typical
or preferred process conditions (i.e., reaction temperatures,
times, mole ratios of reactants, solvents, pressures, etc.) are
given, other process conditions can also be used unless otherwise
stated. Optimum reaction conditions may vary with the particular
reactants or solvent used, but such conditions can be determined by
one skilled in the art by routine optimization procedures.
[0210] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group, as well as suitable conditions for protection and
deprotection, are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in T. W. Greene and P. G. M. Wuts, Protecting Groups in
Organic Synthesis, Second Edition, Wiley, New York, 1991, and
references cited therein.
[0211] The compounds provided herein may be isolated and purified
by known standard procedures. Such procedures include (but are not
limited to) recrystallization, column chromatography or HPLC. The
compounds provided herein may be prepared from known or
commercially available starting materials and reagents by one
skilled in the art of organic synthesis.
[0212] The enantiomerically pure compounds provided herein may be
prepared according to any techniques known to those of skill in the
art. For instance, they may be prepared by chiral or asymmetric
synthesis from a suitable optically pure precursor, or obtained
from a racemate by any conventional technique, for example, by
chromatographic resolution using a chiral column, TLC or by the
preparation of diastereoisomers, separation thereof and
regeneration of the desired enantiomer. See, e.g., "Enantiomers,
Racemates and Resolutions," by J. Jacques, A. Collet, and S. H.
Wilen, (Wiley-Interscience, New York, 1981); S. H. Wilen, A.
Collet, and J. Jacques, Tetrahedron, 2725 (1977); E. L. Eliel
Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and S.
H. Wilen Tables of Resolving Agents and Optical Resolutions 268 (E.
L. Eliel ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972,
Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H.
Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.), and
Stereoselective Synthesis A Practical Approach, Mihaly Nogradi
(1995 VCH Publishers, Inc., NY, N.Y.).
[0213] In certain embodiments, an enantiomerically pure compound of
formula (I) may be obtained by reaction of the racemate with a
suitable optically active acid or base. Suitable acids or bases
include those described in Bighley et al., 1995, Salt Forms of
Drugs and Adsorption, in Encyclopedia of Pharmaceutical Technology,
vol. 13, Swarbrick & Boylan, eds., Marcel Dekker, New York; ten
Hoeve & H. Wynberg, 1985, Journal of Organic Chemistry
50:4508-4514; Dale & Mosher, 1973, J. Am. Chem. Soc. 95:512;
and CRC Handbook of Optical Resolution via Diastereomeric Salt
Formation, the contents of which are hereby incorporated by
reference in their entireties.
[0214] Enantiomerically pure compounds can also be recovered either
from the crystallized diastereomer or from the mother liquor,
depending on the solubility properties of the particular acid
resolving agent employed and the particular acid enantiomer used.
The identity and optical purity of the particular compound so
recovered can be determined by polarimetry or other analytical
methods known in the art. The diasteroisomers can then be
separated, for example, by chromatography or fractional
crystallization, and the desired enantiomer regenerated by
treatment with an appropriate base or acid. The other enantiomer
may be obtained from the racemate in a similar manner, or worked up
from the liquors of the first separation. In certain embodiments,
enantiomerically pure compound can be separated from racemic
compound by chiral chromatography. Various chiral columns and
eluents for use in the separation of the enantiomers are available
and suitable conditions for the separation can be empirically
determined by methods known to one of skill in the art. Examples of
chiral columns available for use in the separation of the
enantiomers provided herein include, but are not limited to,
CHIRALCEL.RTM. OB, CHIRALCEL.RTM. OB-H, CHIRALCEL.RTM. OD,
CHIRALCEL.RTM. OD-H, CHIRALCEL.RTM. OF, CHIRALCEL.RTM. OG,
CHIRALCEL.RTM. OJ and CHIRALCEL.RTM. OK.
[0215] Compounds disclosed herein may be obtained via the general
synthetic methods illustrated in the synthetic schemes presented
herein. General synthetic methods useful in the synthesis of
compounds, precursors, and starting materials described herein are
available in the art. Starting materials useful for preparing
compounds and intermediates thereof, and/or practicing methods
described herein, are commercially available or may be prepared by
well-known synthetic methods.
[0216] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups or protecting strategies may be
necessary to prevent certain functional groups from undergoing
undesired reactions. Suitable protecting groups for various
functional groups as well as suitable conditions for protecting and
protecting particular functional groups are well known in the
art.
[0217] It will be appreciated that where typical or preferred
process conditions, e.g., reaction temperatures, reaction times,
molar ratios of reactants, solvents, pressures, etc., are given
other process conditions may also be used. Optimal reaction
conditions may vary with the particular reactants, solvents,
functional groups, and protecting groups used, but such conditions
may be determined by one skilled in the art by routine optimization
procedures.
[0218] Furthermore, certain compounds provided by the present
disclosure will contain one or more stereogenic centers.
Accordingly, and if desired, such compounds may be prepared or
isolated as pure stereoisomers, e.g., as individual enantiomers,
diastereomers, atropisomers, rotamers, or as stereoisomer enriched
mixtures or racemates. All such stereoisomers are included within
the scope of this disclosure. Pure stereoisomers (or enriched
mixtures thereof) may be prepared using, for example, optically
active starting materials, stereoselective reagents such as chiral
catalysts and auxiliaries well known in the art. Alternatively,
racemic mixtures of such compounds may be separated or partially
enriched using, for example, chromatographic methods with chiral
stationary phases, chiral resolving agents, and the like.
Diastereomers may be separated by physical methods such as
chromatography or crystallization.
[0219] The methods presented in the schemes provided by the present
disclosure are illustrative rather than comprehensive.
[0220] A compound of formula (I) or a pharmaceutically acceptable
salt or solvate or hydrate thereof may be provided according to
Scheme 1.
##STR00028##
wherein X, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5a, R.sup.5b,
R.sup.5c, R.sup.5d, and R.sup.5e are as described herein.
Representative Synthesis of Starting Carbonates of Formula (II)
[0221] The starting carbonate compounds of formula (II) may be
prepared by reacting the appropriate phenol with the appropriate
chloroformate as described below.
Description 1-1
1-Chloroethyl 2-fluorophenyl carbonate (D1-1)
##STR00029##
[0222] Method A
[0223] 2-Fluorophenol (4.87 g) and chloroethyl chloroformate (6.2
ml) were mixed in acetonitrile (25 ml) at 0.degree. C.
Triethylamine (7.9 ml) was slowly added while keeping the reaction
temperature .ltoreq.10.degree. C. The reaction mixture was stirred
for approximately 5 minutes at .ltoreq.10.degree. C., then warmed
up to room temperature (.about.22.degree. C.). The reaction was
stirred at .about.22.degree. C. for one hour. The solid in the
reaction was filtered and the filtrate was distilled to remove
acetonitrile. The reaction mixture was then extracted with
tert-butyl methyl ether (50 ml) and water (20 ml) to remove
triethylamine hydrochloride salt. Distillation to remove solvents
yielded the title compound (9.71 g).
Method B
[0224] 2-Fluorophenol (7.08 g) and chloroethyl chloroformate (13.90
g) were mixed in ethyl acetate (170 ml) under a nitrogen
atmosphere. The mixture was cooled to -20.degree. C. Triethylamine
(9.7 ml) was slowly added to the reaction over 40 minutes while
keeping temperature at .ltoreq.-15.degree. C. The reaction was
warmed to -5.degree. C., and stirred for 1 hour. The solid in the
reaction was filtered and washed with ethyl acetate (20 ml). The
combined ethyl acetate solution was washed with water (50 ml)
twice. Solvents and excess chloroethyl chloroformate were distilled
off under reduced pressure to yield the title compound (14.1
g).
Method C
[0225] To a 1 L jacketed laboratory reactor was charged water (700
ml), sodium bicarbonate (72.0 grams). The mixture was cooled to
0.degree. C. A premixed solution containing 2-fluorophenol (60.0
grams) and chloroethyl chloroformate (80.3 grams) was slowly added
to the reaction over 1 hour. The reaction was stirred at 0.degree.
C. for 2.5 hours. Heptane (400 ml) was added to the reaction. The
reaction temperature was warmed up to 20.degree. C. After 20
minutes stirring, the aqueous layer was removed. The heptane
solution was washed with water (250 ml) twice. Heptane and excess
chloroethyl chloroformate were distilled out at 30-40.degree. C.
under reduced pressure to yield the title compound as an oil (113.1
g).
Description 1-2
1-Chloroethyl 3-fluorophenyl carbonate (D1-2)
##STR00030##
[0227] 3-Fluorophenol (5.78 g) and dichloromethane (60 ml) were
charged to reactor, followed by chloroethyl chloroformate (7.74 g).
The reaction mixture was cooled to 0.degree. C. Triethylamine (7.6
ml) was added slowly whilst maintaining the reaction temperature
.ltoreq.20.degree. C. The reaction mixture was warmed to room
temperature, and stirred overnight. The reaction mixture was washed
by water (50 ml) twice to remove triethylamine hydrochloride salt.
Solvents and excess chloroethyl chloroformate were distilled off
under reduced pressure to yield the title compound (10.7 g).
Description 1-3
1-Chloroethyl 4-fluorophenyl carbonate (D1-3)
##STR00031##
[0229] 4-Fluorophenol (5.79 g) and dichloromethane (60 ml) were
charged to reactor, followed by chloroethyl chloroformate (7.75 g).
The reaction mixture was cooled to 0.degree. C. Triethylamine (7.6
ml) was added slowly whilst maintaining the reaction temperature
.ltoreq.20.degree. C. The reaction mixture was warmed to room
temperature, and stirred overnight. The reaction mixture was washed
by water (40 ml) twice to remove triethylamine hydrochloride salt.
Solvents and excess chloroethyl chloroformate were distilled off
under reduced pressure to yield the title compound (11.1 g).
Description 1-4
1-Chloroethyl 2,6-difluorophenyl carbonate (D1-4)
##STR00032##
[0231] To a solution of 2,6-difluoro-phenol (8.7 g) in
dichloromethane (80 ml) was added chloroethyl chloroformate (7.6
ml). The mixture was cooled to 0.degree. C. Triethylamine (9.8 ml)
was added slowly whilst maintaining the reaction temperature
.ltoreq.20.degree. C. The reaction was warmed up to room
temperature and stirred for 1 hour. The reaction mixture was washed
with water (60 ml) twice. Dichloromethane was distilled out to give
a light oil product, which solidified to an off-white solid upon
standing. Heptane (20 ml) was added to the crude product. After
stiffing for 2 hours at 0.degree. C., the slurry was filtered to
yield the title compound as a white crystalline solid (14.8 g).
Description 1-5
1-Chloroethyl 2-chlorophenyl carbonate (D1-5)
##STR00033##
[0233] Water (4343.5 ml) and K.sub.2CO.sub.3 (1120.7 g) were
charged to a 16 L jacketed laboratory reactor. The vessel contents
were cooled to 0.degree. C. A premixed solution of 2-chlorophenol
(868.7 g) and 1-chloroethyl chloroformate (1159.3 g) in toluene
(868.7 ml) were added to the vessel using a separate addition
funnel over 52 minutes. The temperature of the vessel contents was
maintained between -1.degree. C. and 2.2.degree. C. during the
addition. After a further 2 hours 40 minutes (approx), the reaction
was quenched by addition of aqueous ammonia hydroxide (28-30% as
ammonia; 23 g). Toluene (5212.2 ml) was added and the mixture was
stirred for 30 minutes. The aqueous layer was drained and the
organic layer was washed in 2.6 L water.
[0234] The organic layer was maintained at 5.degree. C. overnight.
The organic layer was then distilled. The vessel contents were then
washed with water, acetone and toluene. The mixture was
concentrated on a rotovap at 50.degree. C., then on a high vac
overnight at room temperature to yield the title compound.
Description 1-6
1-Chloroethyl 3-(methyloxy)phenyl carbonate (D1-6)
##STR00034##
[0236] A solution of diethyl carbonate (0.93 vol) in
N,N-diisopropylethylamine (1.47 vol, 1.05 eq) is prepared and
cooled to 5.degree. C. A solution of 3-methoxyphenol (1 wt, 1 eq)
in 2M NaOH (4.23 vol, 1.05 eq) is prepared and cooled to 5.degree.
C. The diethyl carbonate and 3-methoxyphenol solutions are combined
using a t-piece and fed directly into the loop of the loop reactor.
1-Chloroethylchloroformate (1.05 eq) is added via the centrifugal
pump inlet to give a total residence time of 5-15 min. The outlet
of the reactor is passed through a tube reactor (5-15 min residence
time) held at 5.degree. C. The process stream is separated in a
phase separator or CLLE where the phases separate at ambient
temperature with the organic phase at the top and the aqueous phase
at the bottom.
[0237] The volumetric ratio of organic to aqueous is .about.2:3 at
all times.
[0238] Percent yield range observed following the method of
Description 1-6: >95%.
Description 1-7
1-Chloroethyl 2-trifluoromethylphenyl carbonate (D1-7)
##STR00035##
[0240] 2-Trifluoromethylphenol (50 mmol) and chloroethyl
chloroformate (6.2 ml) are mixed in acetonitrile (25 ml) at
0.degree. C. Triethylamine (7.9 ml) is slowly charged while keeping
the reaction temperature .ltoreq.10.degree. C. The reaction mixture
is stirred for approximately 5 minutes at .ltoreq.10.degree. C.,
then warmed up to room temperature (.about.22.degree. C.). The
reaction is stirred at .about.22.degree. C. for one hour. The solid
in the reaction is filtered and the filtrate is distilled to remove
acetonitrile. The reaction mixture is then extracted with
tert-butyl methyl ether (50 ml) and water (20 ml) to remove
triethylamine hydrochloride salt. Distillation to remove solvents
yields the title compound.
[0241] 1-Chloroethyl 3-trifluoromethylphenyl carbonate (D1-8) and
1-chloroethyl 4-trifluoromethylphenyl carbonate (D1-9) can be
prepared using the appropriate reagents and following the method
described for D1-7.
Description 1-10
1-Chloroethyl 4-methoxycarbonylphenyl carbonate (D1-10)
##STR00036##
[0243] 4-Hydroxybenzoic acid methyl ester (45 mmol) and chloroethyl
chloroformate (6.2 ml) are mixed in acetonitrile (25 ml) at
0.degree. C. Triethylamine (7.9 ml) is slowly charged while keeping
the reaction temperature .ltoreq.10.degree. C. The reaction mixture
is stirred for approximately 5 minutes at .ltoreq.10.degree. C.,
then warmed up to room temperature (.about.22.degree. C.). The
reaction is stirred at .about.22.degree. C. for one hour. The solid
in the reaction is filtered and the filtrate is distilled to remove
acetonitrile. The reaction mixture is then extracted with
tert-butyl methyl ether (50 ml) and water (20 ml) to remove
triethylamine hydrochloride salt. Distillation to remove solvents
yields the title compound.
[0244] 1-Chloroethyl 2-methoxycarbonylphenyl carbonate (D1-11) and
1-chloroethyl 3-methoxycarbonylphenyl carbonate (D1-12) can be
prepared using the appropriate reagents and following the method
described for D1-10.
Description 1-13
1-Chloroethyl 3,4-methylenedioxyphenyl carbonate (D1-13)
##STR00037##
[0246] 3,4-Methylenedioxyphenol (50 mmol) and chloroethyl
chloroformate (6.0 ml) are mixed in acetonitrile (25 ml) at
0.degree. C. Triethylamine (7.7 ml) is slowly charged while keeping
the reaction temperature .ltoreq.10.degree. C. The reaction mixture
is stirred for approximately 5 minutes at .ltoreq.10.degree. C.,
then warmed up to room temperature (.about.22.degree. C.). The
reaction is stirred at .about.22.degree. C. for one hour. The solid
in the reaction is filtered and the filtrate is distilled to remove
acetonitrile. The reaction mixture is then extracted with
tert-butyl methyl ether (50 ml) and water (20 ml) to remove
triethylamine hydrochloride salt. Distillation to remove solvents
yields the title compound.
[0247] 1-Chloroethyl 2,3-methylenedioxyphenyl carbonate (D1-14) can
be prepared using the appropriate reagent and following the method
described for D1-13.
Description 1-15
1-Chloroethyl 3,4-ethylenedioxyphenyl carbonate (D1-15)
##STR00038##
[0249] 3,4-Ethylenedioxyphenol (25 mmol) and chloroethyl
chloroformate (3.0 ml) are mixed in acetonitrile (25 ml) at
0.degree. C. Triethylamine (3.9 ml) is slowly charged while keeping
the reaction temperature .ltoreq.10.degree. C. The reaction mixture
is stirred for approximately 5 minutes at .ltoreq.10.degree. C.,
then warmed up to room temperature (.about.22.degree. C.). The
reaction is stirred at .about.22.degree. C. for one hour. The solid
in the reaction is filtered and the filtrate is distilled to remove
acetonitrile. The reaction mixture is then extracted with
tert-butyl methyl ether (50 ml) and water (20 ml) to remove
triethylamine hydrochloride salt. Distillation to remove solvents
yields the title compound.
[0250] 1-Chloroethyl 2,3-ethylenedioxyphenyl carbonate (D1-16) can
be prepared using the appropriate reagent and following the method
described for D1-15.
[0251] The following compounds can be prepared by following the
method described above.
##STR00039## ##STR00040##
Representative Synthesis of Carbonates of Formula (III) (Step
A)
[0252] The carbonate compounds of formula (III) may be prepared by
reacting the carbonate of formula (II) with the appropriate
carboxylic acid as described below.
Description 2-1
1-({[(2-Fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate
(D2-1)
##STR00041##
[0253] Method A
[0254] To a reaction vessel equipped with a Dean-Stark trap and
reflux condenser was charged 1-chloroethyl 2-fluorophenyl carbonate
(may be prepared as described in Description 1-1; 22.10 g), heptane
(68 ml) and Cu.sub.2O (10.80 g) under nitrogen atmosphere, followed
by isobutyric acid (67 ml). The reactor was degassed by nitrogen.
The reaction was heated to 115-120.degree. C. and stirred for 3-5
hrs. The reaction mixture was then cooled to <50.degree. C. The
solids in the reaction were filtered and washed with heptane (80
ml). The filtrate and the heptane wash were combined. Water (100
ml) was added to the mixture. The mixture was cooled to 0.degree.
C. A dilute aqueous solution of ammonium hydroxide (10-15%, 90 ml)
was slowly added to the mixture while keeping the temperature below
15.degree. C. to adjust the pH of the mixture, which was adjusted
to 9.5-10. After mixing for 10 minutes and settling for 10 minutes,
the aqueous layer was removed. The organic layer was washed with
water (80 ml). The solvents were distilled out to dryness to yield
the title compound as an oil (24.3 g).
Method B
[0255] To a mixture of 1-chloroethyl 2-fluorophenyl carbonate (may
be prepared as described in Description 1-1; 0.58 g) and isobutyric
acid (2.0 ml) was added silver isobutyrate (0.78 g). The mixture
was heated to 90.degree. C. for one hour. The reaction was then
cooled to room temperature and filtered. The reactor and filter
cake were washed with dichloromethane (10 ml). The combined
filtrate and wash were distilled under reduced pressure until all
isobutyric acid and solvents were removed to yield the title
compound as an oil (0.58 g).
Description 2-2
1-({[(3-Fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate
(D2-2)
##STR00042##
[0257] To a reaction vessel under nitrogen atmosphere was charged
1-chloroethyl 3-fluorophenyl carbonate (may be prepared as
described in Description 1-2; 21.8 g), isobutyric acid (80 ml) and
Cu.sub.2O (15.0 g). The reactor was degassed by nitrogen. The
reaction was heated to 115-120.degree. C. and stirred for 3-5 hrs.
The reaction mixture was then was cooled to <50.degree. C. The
solids in the reaction were filtered and washed with heptane (160
ml). The filtrate and the heptane wash were combined. Water (100
ml) was added to the mixture. The mixture was cooled to 0.degree.
C. A dilute aqueous solution of ammonium hydroxide (.about.15%) was
slowly added to the mixture while keeping the temperature below
15.degree. C. to adjust the pH of the mixture to 9.5-10. After
mixing for 10 minutes and settling for 10 minutes, the aqueous
layer was removed. The organic layer was separated and washed with
water (110 ml). The solvents were distilled out to dryness to yield
the title compound as an oil (20.3 g).
Description 2-3
1-({[(4-Fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate
(D2-3)
##STR00043##
[0259] To a reaction vessel under nitrogen atmosphere was charged
1-chloroethyl 4-fluorophenyl carbonate (may be prepared as
described in Description 1-3; 24.4 g), isobutyric acid (100 ml) and
Cu.sub.2O (16.8 g). The reactor was degassed by nitrogen. The
reaction was heated to 100-110.degree. C. and stirred for 4 hrs.
When the reaction was complete as determined by HPLC, it was cooled
to 20.degree. C. The solids in the reaction were filtered and
washed with heptane (100 ml). The filtrate and the heptane wash
were combined. Water (100 ml) was added to the mixture. The mixture
was cooled to 0.degree. C. A dilute aqueous solution of ammonium
hydroxide (-15%) was slowly added to the mixture while keeping the
temperature below 15.degree. C. to adjust the pH of the mixture,
which was adjusted to 9.5-10. After mixing for 10 minutes and
settling for 10 minutes, the aqueous layer was removed. The organic
layer was washed with water (150 ml). The solvents were distilled
out to dryness to yield the title compound as an oil (24.6 g).
Description 2-4
1-({[(2,6-Difluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate
(D2-4)
##STR00044##
[0261] To a solution of 1-chloroethyl 2,6-difluorophenyl carbonate
(may be prepared as described in Description 1-4; 0.1 g) in
isobutyric acid (1.0 ml) was added silver isobutyrate (0.2 g). The
mixture was heated to 90.degree. C. for 3 hours. The reaction was
then cooled to room temperature and filtered. The reactor and
filter cake were washed with dichloromethane (10 ml). The combined
filtrate and the wash were distilled under reduced pressure until
all isobutyric acid and solvents were removed to yield the title
compound as an oil (0.2 g).
Description 2-5
1-({[(2-Chlorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate
(D2-5)
##STR00045##
[0263] Add Cu.sub.2O, o-xylene, isobutyric acid, and isobutyric
anhydride to a 1 L jacketed laboratory reactor sequentially in
quick succession. Purge atmosphere immediately by pulling vacuum
and backfilling with N.sub.2 over three cycles. Heat the mixture to
120.degree. C. and stir overnight at this temperature. Add
1-chloroethyl 2-chlorophenyl carbonate (may be prepared as
described in Description 1-5) via syringe while maintaining the
temperature of the reaction .gtoreq.105.degree. C. Stir at
120.degree. C. for 3 h or until HPLC indicates <0.5% PAR
1-chloroethyl 2-chlorophenyl carbonate. Cool the mixture to
20.degree. C. and filter off the copper salt. Add o-xylene and
water and neutralize the solution with NH.sub.4OH (aq) to a final
pH of 9.5-10. Drain off the aqueous layer and wash the organic
layer with NH.sub.4OH (aq). Drain off the aqueous layer and wash
the organic layer with water. Pass through a polishing filter.
Distill to minimum stir in jacketed laboratory reactor to yield the
title compound (93%).
Description 2-6
1-[({[3-(Methyloxy)phenyl]oxy}carbonyl)oxy]ethyl 2-methylpropanoate
(D2-6)
##STR00046##
[0265] A solution of N,N-diisopropylethylamine (0.604 vol, 0.8 eq),
iso-butyric acid (4.02 vol, 10 eq) and n-tetrabutylammonium bromide
(0.14 wt, 0.1 eq) is heated to 105.+-.5.degree. C. before a
solution of 1-chloroethyl 3-(methyloxy)phenyl carbonate (may be
prepared as described in Description 1-6; 1.0 wt) is added. The
resulting solution is heated at 105.+-.5.degree. C. for ca. 120
minutes or until the reaction is deemed complete by HPLC, before
being cooled to 20.+-.5.degree. C.
[0266] The resulting reaction mixture is diluted with water (0.6
vol) before being diluted with tert-butyl methyl ether (8 vol). The
resulting mixture is then washed with 5M NaOH (12 eq) counter
currently through 3 stages in a CLLE at a rate of 3 g min.sup.-1.
The resulting organic phase is then washed with 0.5 M
H.sub.2SO.sub.4 (1.9 eq) in the fourth stage of the CLLE before
being washed with water (8 vol) in the final stage. The tert-butyl
methyl ether phase is concentrated under atmospheric distillation
to yield the title compound.
Description 2-7
1-({[(2-Trifluoromethylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (D2-7)
##STR00047##
[0268] To a reaction vessel under nitrogen atmosphere is charged
1-chloroethyl 2-trifluoromethylphenyl carbonate (may be prepared as
described in Description 1-7; 100 mmol), isobutyric acid (80 ml)
and Cu.sub.2O (15.0 g). The reactor is degassed by nitrogen. The
reaction is heated to 115-120.degree. C. and stirred for 3-5 hrs.
The reaction mixture is then cooled to <50.degree. C. The solids
in the reaction are filtered and washed with heptane (160 ml). The
filtrate and the heptane wash are combined. Water (100 ml) is added
to the mixture. The mixture is cooled to 0.degree. C. A dilute
aqueous solution of ammonium hydroxide (.about.15%) is slowly added
to the mixture while keeping the temperature below 15.degree. C. to
adjust the pH of the mixture to 9.5-10. After mixing for 10 minutes
and settling for 10 minutes, the aqueous layer is removed. The
organic layer is washed with water (110 ml). The solvents are
distilled out to dryness to yield the title compound.
Description 2-8
1-({[(3-Trifluoromethylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (D2-8)
##STR00048##
[0270] To a reaction vessel under nitrogen atmosphere is charged
1-chloroethyl 3-trifluoromethylphenyl carbonate (may be prepared as
described in Description 1-8; 100 mmol), isobutyric acid (80 ml)
and Cu.sub.2O (15.0 g). The reactor is degassed by nitrogen. The
reaction is heated to 115-120.degree. C. and stirred for 3-5 hrs.
The reaction mixture is then cooled to <50.degree. C. The solids
in the reaction are filtered and washed with heptane (160 ml). The
filtrate and the heptane wash are combined. Water (100 ml) is added
to the mixture. The mixture is cooled to 0.degree. C. A dilute
aqueous solution of ammonium hydroxide (.about.15%) is slowly added
to the mixture while keeping the temperature below 15.degree. C. to
adjust the pH of the mixture to 9.5-10. After mixing for 10 minutes
and settling for 10 minutes, the aqueous layer is removed. The
organic layer is washed with water (110 ml). The solvents are
distilled out to dryness to yield the title compound.
Description 2-9
1-({[(3-Trifluoromethylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (D2-9)
##STR00049##
[0272] To a reaction vessel under nitrogen atmosphere is charged
1-chloroethyl 2-trifluoromethylphenyl carbonate (may be prepared as
described in Description 1-9; 100 mmol), isobutyric acid (80 ml)
and Cu.sub.2O (15.0 g). The reactor is degassed by nitrogen. The
reaction is heated to 115-120.degree. C. and stirred for 3-5 hrs.
The reaction mixture is then cooled to <50.degree. C. The solids
in the reaction are filtered and washed with heptane (160 ml). The
filtrate and the heptane wash are combined. Water (100 ml) is added
to the mixture. The mixture is cooled to 0.degree. C. A dilute
aqueous solution of ammonium hydroxide (.about.15%) is slowly added
to the mixture while keeping the temperature below 15.degree. C. to
adjust the pH of the mixture to 9.5-10. After mixing for 10 minutes
and settling for 10 minutes, the aqueous layer is removed. The
organic layer is washed with water (110 ml). The solvents are
distilled out to dryness to yield the title compound.
Description 2-10
1-({[(4-Methoxycarbonylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (D2-10)
##STR00050##
[0274] To a reaction vessel under nitrogen atmosphere is charged
1-chloroethyl 4-methoxycarbonylphenyl carbonate (may be prepared as
described in Description 1-10; 100 mmol), isobutyric acid (80 ml)
and Cu.sub.2O (15.0 g). The reactor is degassed by nitrogen. The
reaction is heated to 115-120.degree. C. and stirred for 3-5 hrs.
The reaction mixture is then cooled to <50.degree. C. The solids
in the reaction are filtered and washed with heptane (160 ml). The
filtrate and the heptane wash are combined. Water (100 ml) is added
to the mixture. The mixture is cooled to 0.degree. C. A dilute
aqueous solution of ammonium hydroxide (.about.15%) is slowly added
to the mixture while keeping the temperature below 15.degree. C. to
adjust the pH of the mixture to 9.5-10. After mixing for 10 minutes
and settling for 10 minutes, the aqueous layer is removed. The
organic layer is washed with water (110 ml). The solvents are
distilled out to dryness to yield the title compound.
[0275] 1-({[(2-Methoxycarbonylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (D2-11) and
1-({[(3-Methoxycarbonylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (D2-10) (D2-12) can be prepared using the
appropriate reagents and following the method described for
D2-10.
Description 2-13
1-({[(3,4-Methylenedioxyphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (D2-13)
##STR00051##
[0277] To a reaction vessel under nitrogen atmosphere is charged
1-chloroethyl 3,4-methylenedioxyphenyl carbonate (may be prepared
as described in Description 1-13; 100 mmol), isobutyric acid (80
ml) and Cu.sub.2O (15.0 g). The reactor is degassed by nitrogen.
The reaction is heated to 115-120.degree. C. and stirred for 3-5
hrs. The reaction mixture is then cooled to <50.degree. C. The
solids in the reaction are filtered and washed with heptane (160
ml). The filtrate and the heptane wash are combined. Water (100 ml)
is added to the mixture. The mixture is cooled to 0.degree. C. A
dilute aqueous solution of ammonium hydroxide (.about.15%) is
slowly added to the mixture while keeping the temperature below
15.degree. C. to adjust the pH of the mixture to 9.5-10. After
mixing for 10 minutes and settling for 10 minutes, the aqueous
layer is removed. The organic layer is washed with water (110 ml).
The solvents are distilled out to dryness to yield the title
compound.
[0278] 1-({[(2,3-methylenedioxyphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (D2-14) can be prepared using the appropriate
reagents and following the method described for D2-13.
Description 2-15
1-({[(3,4-Methylenedioxyphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (D2-15)
##STR00052##
[0280] To a reaction vessel under nitrogen atmosphere is charged
1-chloroethyl 3,4-ethylenedioxyphenyl carbonate (may be prepared as
described in Description 1-13; 100 mmol), isobutyric acid (80 ml)
and Cu.sub.2O (15.0 g). The reactor is degassed by nitrogen. The
reaction is heated to 115-120.degree. C. and stirred for 3-5 hrs.
The reaction mixture is then cooled to <50.degree. C. The solids
in the reaction are filtered and washed with heptane (160 ml). The
filtrate and the heptane wash are combined. Water (100 ml) is added
to the mixture. The mixture is cooled to 0.degree. C. A dilute
aqueous solution of ammonium hydroxide (.about.15%) is slowly added
to the mixture while keeping the temperature below 15.degree. C. to
adjust the pH of the mixture to 9.5-10. After mixing for 10 minutes
and settling for 10 minutes, the aqueous layer is removed. The
organic layer is washed with water (110 ml). The solvents are
distilled out to dryness to yield the title compound.
[0281] 1-({[(2,3-ethylenedioxyphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (D2-16) can be prepared using the appropriate
reagents and following the method described for compound D2-15.
[0282] The following compounds can be prepared by following the
methods described above.
##STR00053## ##STR00054## ##STR00055##
Representative Preparation of Pure Isomers of Carbonates of Formula
(III)
[0283] The pure enantiomers of carbonate compounds of formula (III)
may be prepared by enzymatic methods or other conventional methods
known to one skilled in the art. For example, the R-isomer of the
carbonate may be prepared by enzymatic reaction of, or resolution
of, a carbonate of formula (III) with lipase or other suitable
enzymes as described in U.S. Pat. No. 7,872,046 or in U.S. Pat. No.
8,062,870.
Description 3-1
1(R)-({[(2-Fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate
(D3-1)
##STR00056##
[0285] 1-({[(2-Fluorophenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (D2-1), prepared as described above (200 g) and
lipase from Candida antarctica, immobilized on acrylic resin, (8.0
g) is stirred in phosphate buffered saline, pH 7.2, (1.6 L) at room
temperature. The progress of the reaction is monitored by
.sup.1H-NMR using the chiral solvating agent
[(R)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol] and is complete
within 8-20 h. The reaction mixture is diluted with diethyl ether
and the diethyl ether layer separated and filtered through a pad of
Celite to remove the enzyme. The ether phase is washed repeatedly
with water then brine, and dried over anhydrous Na.sub.2SO.sub.4.
Removal of the solvent in vacuo affords the title compound
(D3-1).
[0286] The following compounds can be prepared by following the
method described for compound D3-1 and using the appropriate
starting materials.
##STR00057## ##STR00058## ##STR00059##
Description 3-22
1(S)-({[(2-Fluorophenyl)oxy]carbonyl}oxy)-2-methylpropyl
2-methylpropanoate (D3-22)
##STR00060##
[0288] A suspension of enzyme (5-10% by weight) in 50 mM pH 7.2
phosphate buffer (45 mL) and the racemic carbonate (D2-17) (10
mmol) in isopropyl ether (5 mL) is shaken on an orbital shaker at
room temperature (25.degree. C.). The reaction is monitored by
.sup.1H-NMR using chiral solvating agent. After the reaction is
complete the reaction mixture is filtered through a pad of
CELITE.RTM. 545, followed by extraction with methyl-tert-butyl
ether (MTBE). The organic layer is separated, washed with water and
brine, and dried over anhydrous sodium sulfate (Na.sub.2SO.sub.4).
The removal of the solvents under vacuo yields the corresponding
enzymatically resolved D3-17 carbonate.
[0289] The following compounds can be prepared by following the
method described for compound D3-22 and using the appropriate
starting materials.
##STR00061## ##STR00062## ##STR00063##
Representative Synthesis of Compounds of Formula (I) (Step B)
[0290] The carbamate compounds of formula (I) may be prepared by
reacting the carbonate of formula (III) with the appropriate amine
as described below.
Example 1
1-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid (E1)
##STR00064##
[0291] Method A
[0292] To a jacketed laboratory reactor was charged
1-({[(2-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate (may
be prepared as described in Description 2-1; 20.0 g) in heptanes
solution (40 ml). Gabapentin (13.94 g), water (40 ml) and
acetonitrile (30 ml) were charged and stirred for 10 minutes at
10-20.degree. C. Triethylamine (11.4 ml) was charged over 5
minutes. The reaction was stirred at 10-20.degree. C. for 4-8 hrs
until 1-({[(2-fluorophenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate was <2% by HPLC. 2 M H.sub.2SO.sub.4 aqueous
solution (20 ml) was charged to acidify the reaction to pH 4-4.5.
Tert-butyl methyl ether (90 ml) was charged and mixed for .about.10
minutes. After removal of aq. layer, the organic layer was washed
with water (30 ml). The solvents were stripped off under reduced
pressure with process temperature .ltoreq.35.degree. C. and reactor
jacket temperature .ltoreq.45.degree. C. Heptane (100 ml) was
charged and stripped off under vacuum. The crude product was used
in crystallization directly.
[0293] Heptane (180 ml) and tert-butyl methyl ether (20 ml) were
charged to the crude product. The mixture was then warmed up to
40-45.degree. C. to achieve a clear solution. The process
temperature was cooled to .about.30.degree. C. over .about.50
minutes. A 3% w/w seed crystal was added. The temperature was
slowly cooled to 15.degree. C. and stayed at 15.degree. C. for
.about.6 hrs. When a significant amount of the product solid came
out of solution (monitored by React-IR), the mixture was slowly
cooled to -2 to 0.degree. C. After holding at -2 to 0.degree. C.
for 9 hrs, the mixture was filtered and washed w/ heptane (60 ml)
and heptane/tert-butyl methyl ether (10:1) (60 ml). The wet cake
was dried at 25-30.degree. C. under high vacuum overnight. A white
crystalline product (17.08 grams, 80% yield) was obtained.
Method B
[0294] To a jacketed laboratory reactor was charged
1-({[(3-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate (may
be prepared as described in Description 2-2; 10.06 g) and
tert-butyl methyl ether (20 ml). Gabapentin (7.65 g), water (20 ml)
and acetonitrile (15 ml) were charged and stirred for .about.10
minutes at 10-20.degree. C. Triethylamine (6.2 ml) was charged over
.about.5 minutes. The reaction was stirred at 10-20.degree. C. for
5 hrs. 10% potassium hydrogensulfate aqueous solution (67 ml) was
charged to acidify reaction to pH 4-4.5. Tert-butyl methyl ether
(80 ml) was charged and mixed for .about.10 minutes. After removal
of aq. layer, the organic layer was washed with water (50 ml). The
solvents were stripped off under reduced pressure with process
temperature .ltoreq.35.degree. C. and reactor jacket temperature
.ltoreq.45.degree. C. Methylcyclohexane (50 ml) was charged and
stripped off under vacuum. The crude product was used in
crystallization directly.
[0295] Heptane (92 ml) and tert-butyl methyl ether (10 ml) were
charged to the crude product. The mixture was then warmed up to
40-45.degree. C. to achieve a clear solution. The process
temperature was cooled to .about.30.degree. C. over .about.50
minutes. A 3% w/w seed crystal was added. The temperature was
slowly cooled to 15.degree. C. and stayed at 15.degree. C. for
.about.6 hrs. When a significant amount of the product solid came
out of solution (monitored by React-IR), the mixture was slowly
cooled to -2 to 0.degree. C. After holding at -2 to 0.degree. C.
for .about.9 hrs, the mixture was filtered and washed w/ heptane
(40 ml) and heptane/tert-butyl methyl ether (10:1) (30 ml). The wet
cake was dried at 25-30.degree. C. under high vacuum overnight. A
white crystalline product (10.6 grams, 83% yield) was obtained.
Method C
[0296] To a jacketed laboratory reactor was charged
1-({[(4-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate (may
be prepared as described in Description 2-3; 10.81 g) and
tert-butyl methyl ether (23 ml). Gabapentin (8.2 g), water (20 ml)
and acetonitrile (20 ml) were charged and stirred for 10 minutes at
20.degree. C. Triethylamine (6.7 ml) was charged over 5 minutes.
The reaction was stirred at 20.degree. C. for 6 hrs. 10% potassium
hydrogensulfate aqueous solution (67 ml) was charged to acidify
reaction to pH 4-4.5. Tert-butyl methyl ether (80 ml) was charged
and mixed for 10 minutes. After removal of aq. layer, the organic
layer was washed with water (35 ml). The solvents were stripped off
under reduced pressure with process temperature .ltoreq.35.degree.
C. and reactor jacket temperature .ltoreq.45.degree. C. Heptane (60
ml) was charged and stripped off under vacuum. The crude product
was used in crystallization directly.
[0297] Heptane (100 ml) and tert-butyl methyl ether (14 ml) were
charged to the crude product. The mixture was then warmed up to
40-45.degree. C. to achieve a clear solution. The process
temperature was cooled to .about.30.degree. C. over .about.50
minutes. A 3% w/w seed crystal was added. The temperature was
slowly cooled to 15.degree. C. and stayed at 15.degree. C. for
.about.6 hrs. When a significant amount of the product solid came
out of solution (monitored by React-IR), the mixture was slowly
cooled to -2 to 0.degree. C. After holding at -2 to 0.degree. C.
for .about.9 hrs, the mixture was filtered and washed w/ heptane
(40 ml) and heptane/tert-butyl methyl ether (10:1) (30 ml). The wet
cake was dried at 25-30.degree. C. under high vacuum overnight. A
white crystalline product (10.6 grams, 83% yield) was obtained.
Method D
[0298] To a reaction vessel was charged
1-({[(2,6-difluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate
(may be prepared as described in Description 2-4; 0.10 g) and
gabapentin (0.15 g) in acetonitrile (0.6 ml) and water (0.2 ml).
The reaction was warmed to 60.degree. C. and stirred for 1-2 hrs.
The desired product was confirmed by LC-MS.
Method E
[0299] Add gabapentin, 1-({[(2-chlorophenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
2-5), and tetrahydrofuran to a 500 ml jacketed laboratory reactor.
Cool suspension to 15.degree. C. Add NaOH (aq), keeping the
reaction temperature .ltoreq.30.degree. C. Stir resulting solution
at 30.degree. C. for 0.5 h or until HPLC indicates <0.5% PAR
1-({[(2-chlorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate. Add
H.sub.2SO.sub.4 (aq), H.sub.2O, and toluene, keeping the
temperature of the reaction .ltoreq.30.degree. C. Cool to
20.degree. C. and separate layers. Extract aqueous layer with
toluene. To aqueous layer, add H.sub.2SO.sub.4 (aq) and tert-butyl
methyl ether, keeping the temperature of the reaction
.ltoreq.25.degree. C. Separate layers and wash organic layer with
H.sub.2O. Separate layers and add methylcyclohexane to organic
layer. Distill at 100 torr, keeping the temperature of the reaction
.ltoreq.40.degree. C. Add methylcyclohexane and distill at 70 torr,
keeping the temperature of the reaction .ltoreq.40.degree. C.
Adjust temperature to 35.degree. C. and add tert-butyl methyl
ether. Add methylcyclohexane and cool to 28.degree. C. Seed with
seed crystals of the title compound and hold at 28.degree. C. for 5
h. Cool to 15.degree. C. at 0.33.degree. C./min and then hold at
15.degree. C. for 1 h. Heat to 28.degree. C. at 0.33.degree. C./min
and then hold at 28.degree. C. for 1 h. Cool to 0.degree. C. at
0.33.degree. C./min and then hold at 0.degree. C. for 1 h. Filter,
washing the cake twice with cold methylcyclohexane. Dry under
vacuum at 35.degree. C.
[0300] Percent yield observed following the method of Example 1,
method E: approximately 74%
Method F
[0301] Gabapentin is dissolved in 4M sodium hydroxide to give
solution A. 1-({[(2-chlorophenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
2-5) is dissolved in tetrahydrofuran to give solution B. Solution A
is combined with additional 4M sodium hydroxide in flow mode before
being combined with solution B at 30.degree. C. in flow mode in a
reactor (residence time ca 1.5 hr).
[0302] The reaction mixture is combined with 2M sulphuric acid and
additional water in flow mode, before a counter-current extraction
with toluene is performed in continuous liquid-liquid extraction
apparatus (typically across three stages). The heavy (aqueous)
phase is combined with 2M sulfuric acid in flow mode, before a
counter-current extraction with tetrahydrofuran and
methylcyclohexane is performed in continuous liquid-liquid
extraction apparatus (typically a single stage). The light
(organic) phase is washed in a counter-current extraction with
water in continuous liquid-liquid extraction apparatus (typically a
single stage).
[0303] The organic (light) phase is combined with methylcyclohexane
and tetrahydrofuran and water are removed by continuous
reduced-pressure distillation at ca 57.degree. C., 230 mbar.
[0304] A continuous cooling crystallisation is performed across
(typically) two stirred-tank crystallisation vessels, with wet
milling in the first reactor to promote nucleation and control
particle size. The first crystallisation vessel is maintained at ca
32.degree. C., with an average residence time of ca 2 hr. The
second crystallisation vessel is maintained at ca 20.degree. C.,
with an average residence time of ca 2 hr.
[0305] A batch filtration is performed in a filter dryer. The damp
cake is washed with methylcyclohexane. The isolated drug substance
is dried at 20.degree. C. (either in nitrogen flow or under
vacuum).
[0306] Percent yield observed following the method of Example 1,
method F: ca 80% th
Method G
[0307] 1-[({[3-(Methoxy)phenyl]oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
2-6; 1 wt.) is dissolved in tetrahydrofuran (5 vol). Gabapentin
(0.75 wt., 1.24 eq.) is then dissolved in 4N NaOH (1.1 vol, 1.24
eq.) and tetramethylguanidine (0.22 vol., 0.495 eq.). The two feeds
are then mixed together at 20.+-.5.degree. C. and stirred at this
temp for ca. 60 mins. A further aliquot of 4N NaOH (0.44 vol) is
added and the reaction mixed for at least 30 mins until the
reaction is deemed complete by HPLC.
[0308] Tert-butyl methyl ether (6 vol) and 0.5M H.sub.2SO.sub.4
(2.67 vol) are then added, the phases allowed to separate and the
aqueous phase is then washed with tert-butyl methyl ether
(2.times.2.5 vol). The aqueous phase is then acidified by the
addition of 0.5M H.sub.2SO.sub.4 (3.37 vol) and extracted by
tert-butyl methyl ether (2.times.2.5 vol). The combined organic
phases are then washed with 0.05M H.sub.2SO.sub.4 (5.0 vol) and
then water (5.0 vol).
[0309] Methylcyclohexane (10 vol) is then added and the mixture
distilled under vacuum (temperature .ltoreq.45.degree. C.,
P.about.0.1-0.2 bar) to remove the tert-butyl methyl ether. The
mixture is then allowed to cool to 20.+-.5.degree. C. and the
product isolated by filtration. The cake is then washed with
methylcyclohexane (2.times.2 vol) and pulled dry. The solid is then
oven dried under vacuum at 40.degree. C.
[0310] Percent yield range observed following the method of Example
1, method G: 60-80% th solution yield.
Method H
[0311] 1-[({[2-Trifluoromethylphenyl]oxy}carbonyl)oxy]ethyl
2-methylpropanoate (may be prepared as described in Description
2-7; 1 wt.) is dissolved in tetrahydrofuran (5 vol). Gabapentin
(0.75 wt., 1.24 eq.) is then dissolved in 4N NaOH (1.1 vol, 1.24
eq.) and tetramethylguanidine (0.22 vol., 0.495 eq.). The two feeds
are then mixed together at 20.+-.5.degree. C. and stirred at this
temp for ca. 60 mins A further aliquot of 4N NaOH (0.44 vol) is
added and the reaction mixed for at least 30 mins until the
reaction is deemed complete by HPLC.
[0312] Tert-butyl methyl ether (6 vol) and 0.5M H.sub.2SO.sub.4
(2.67 vol) are then added, the phases allowed to separate and the
aqueous phase is then washed with tert-butyl methyl ether
(2.times.2.5 vol). The aqueous phase is then acidified by the
addition of 0.5M H.sub.2SO.sub.4 (3.37 vol) and extracted by
tert-butyl methyl ether (2.times.2.5 vol). The combined organic
phases are then washed with 0.05M H.sub.2SO.sub.4 (5.0 vol) and
then water (5.0 vol).
[0313] Methylcyclohexane (10 vol) is then added and the mixture
distilled under vacuum (temperature .ltoreq.45.degree. C.,
P.about.0.1-0.2 bar) to remove the tert-butyl methyl ether. The
mixture is then allowed to cool to 20.+-.5.degree. C. and the
product isolated by filtration. The cake is then washed with
methylcyclohexane (2.times.2 vol) and pulled dry. The solid is then
oven dried under vacuum at 40.degree. C. to yield the title
product.
Method I
[0314] 1-[({[4-Methoxycarbonylphenyl]oxy}carbonyl)oxy]ethyl
2-methylpropanoate (may be prepared as described in Description
2-10; 1 wt.) is dissolved in tetrahydrofuran (5 vol). Gabapentin
(0.75 wt., 1.24 eq.) is then dissolved in 4N NaOH (1.1 vol, 1.24
eq.) and tetramethylguanidine (0.22 vol., 0.495 eq.). The two feeds
are then mixed together at 20.+-.5.degree. C. and stirred at this
temp for ca. 60 mins A further aliquot of 4N NaOH (0.44 vol) is
added and the reaction mixed for at least 30 mins until the
reaction is deemed complete by HPLC.
[0315] Tert-butyl methyl ether (6 vol) and 0.5M H.sub.2SO.sub.4
(2.67 vol) are then added, the phases allowed to separate and the
aqueous phase is then washed with tert-butyl methyl ether
(2.times.2.5 vol). The aqueous phase is then acidified by the
addition of 0.5M H.sub.2SO.sub.4 (3.37 vol) and extracted by
tert-butyl methyl ether (2.times.2.5 vol). The combined organic
phases are then washed with 0.05M H.sub.2SO.sub.4 (5.0 vol) and
then water (5.0 vol).
[0316] Methylcyclohexane (10 vol) is then added and the mixture
distilled under vacuum (temperature .ltoreq.45.degree. C.,
P.about.0.1-0.2 bar) to remove the tert-butyl methyl ether. The
mixture is then allowed to cool to 20.+-.5.degree. C. and the
product isolated by filtration. The cake is then washed with
methylcyclohexane (2.times.2 vol) and pulled dry. The solid is then
oven dried under vacuum at 40.degree. C. to yield the title
product.
Method J
[0317] 1-[({[3,4-Methylenedioxyphenyl]oxy}carbonyl)oxy]ethyl
2-methylpropanoate (may be prepared as described in Description
2-13; 1 wt.) is dissolved in tetrahydrofuran (5 vol). Gabapentin
(0.75 wt., 1.24 eq.) is then dissolved in 4N NaOH (1.1 vol, 1.24
eq.) and tetramethylguanidine (0.22 vol., 0.495 eq.). The two feeds
are then mixed together at 20.+-.5.degree. C. and stirred at this
temp for ca. 60 mins A further aliquot of 4N NaOH (0.44 vol) is
added and the reaction mixed for at least 30 mins until the
reaction is deemed complete by HPLC.
[0318] Tert-butyl methyl ether (6 vol) and 0.5M H.sub.2SO.sub.4
(2.67 vol) are then added, the phases allowed to separate and the
aqueous phase is then washed with tert-butyl methyl ether
(2.times.2.5 vol). The aqueous phase is then acidified by the
addition of 0.5M H.sub.2SO.sub.4 (3.37 vol) and extracted by
tert-butyl methyl ether (2.times.2.5 vol). The combined organic
phases are then washed with 0.05M H.sub.2SO.sub.4 (5.0 vol) and
then water (5.0 vol).
[0319] Methylcyclohexane (10 vol) is then added and the mixture
distilled under vacuum (temperature .ltoreq.45.degree. C.,
P.about.0.1-0.2 bar) to remove the tert-butyl methyl ether. The
mixture is then allowed to cool to 20.+-.5.degree. C. and the
product isolated by filtration. The cake is then washed with
methylcyclohexane (2.times.2 vol) and pulled dry. The solid is then
oven dried under vacuum at 40.degree. C. to yield the title
product.
Method K
[0320] 1-[({[3,4-Ethylenedioxyphenyl]oxy}carbonyl)oxy]ethyl
2-methylpropanoate (may be prepared as described in Description
2-13; 1 wt.) is dissolved in tetrahydrofuran (5 vol). Gabapentin
(0.75 wt., 1.24 eq.) is then dissolved in 4N NaOH (1.1 vol, 1.24
eq.) and tetramethylguanidine (0.22 vol., 0.495 eq.). The two feeds
are then mixed together at 20.+-.5.degree. C. and stirred at this
temp for ca. 60 mins A further aliquot of 4N NaOH (0.44 vol) is
added and the reaction mixed for at least 30 mins until the
reaction is deemed complete by HPLC.
[0321] Tert-butyl methyl ether (6 vol) and 0.5M H.sub.2SO.sub.4
(2.67 vol) are then added, the phases allowed to separate and the
aqueous phase is then washed with tert-butyl methyl ether
(2.times.2.5 vol). The aqueous phase is then acidified by the
addition of 0.5M H.sub.2SO.sub.4 (3.37 vol) and extracted by
tert-butyl methyl ether (2.times.2.5 vol). The combined organic
phases are then washed with 0.05M H.sub.2SO.sub.4 (5.0 vol) and
then water (5.0 vol).
[0322] Methylcyclohexane (10 vol) is then added and the mixture
distilled under vacuum (temperature .ltoreq.45.degree. C.,
P.about.0.1-0.2 bar) to remove the tert-butyl methyl ether. The
mixture is then allowed to cool to 20.+-.5.degree. C. and the
product isolated by filtration. The cake is then washed with
methylcyclohexane (2.times.2 vol) and pulled dry. The solid is then
oven dried under vacuum at 40.degree. C. to yield the title
product.
Example 2
3(S)-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-methylhexanoi-
c acid (F1)
##STR00065##
[0323] Method A
[0324] To a jacketed laboratory reactor is charged
1-({[(2-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate (may
be prepared as described in Description 2-1; 20.0 g) in heptanes
solution (40 ml). Pregabalin (13.3 g), water (40 ml) and
acetonitrile (30 ml) are charged and the mixture is stirred for 10
minutes at 10-20.degree. C. Triethylamine (11.4 ml) is added over 5
minutes. The reaction is stirred at 10-20.degree. C. for 4-8 hrs
until 1-({[(2-fluorophenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate is <2% by HPLC. 2 M H.sub.2SO.sub.4 aqueous
solution (20 ml) is charged to acidify reaction to pH 4-4.5.
Tert-butyl methyl ether (90 ml) is charged and mixed for .about.10
minutes. After removal of aq. layer, the organic layer is washed
with water (30 ml). The solvents are stripped off under reduced
pressure with process temperature .ltoreq.35.degree. C. and reactor
jacket temperature .ltoreq.45.degree. C. to yield the title
product.
Method B
[0325] To a jacketed laboratory reactor is charged
1-({[(3-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate (may
be prepared as described in Description 2-2; 10.06 g) and
tert-butyl methyl ether (20 ml). Pregabalin (7.35 g), water (20 ml)
and acetonitrile (15 ml) are added and the mixture is stirred for
.about.10 minutes at 10-20.degree. C. Triethylamine (6.2 ml) is
charged over 5 minutes. The reaction is stirred at 10-20.degree. C.
for 5 hrs. 10% potassium hydrogensulfate aqueous solution (67 ml)
is charged to acidify reaction to pH 4-4.5. Tert-butyl methyl ether
(80 ml) is charged and mixed for .about.10 minutes. After removal
of aq. layer, the organic layer is washed with water (50 ml). The
solvents are stripped off under reduced pressure with process
temperature .ltoreq.35.degree. C. and reactor jacket temperature
.ltoreq.45.degree. C. to yield the crude title product.
Method C
[0326] To a jacketed laboratory reactor is charged
1-({[(4-trifluoromethylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
2-9; 10.80 g) and tert-butyl methyl ether (20 ml). Pregabalin (7.35
g), water (20 ml) and acetonitrile (15 ml) are added and the
mixture is stirred for .about.10 minutes at 10-20.degree. C.
Triethylamine (6.2 ml) is charged over .about.5 minutes. The
reaction is stirred at 10-20.degree. C. for 5 hrs. 10% potassium
hydrogensulfate aqueous solution (67 ml) is charged to acidify
reaction to pH 4-4.5. Tert-butyl methyl ether (80 ml) is charged
and mixed for .about.10 minutes. After removal of aq. layer, the
organic layer is washed with water (50 ml). The solvents are
stripped off under reduced pressure with process temperature
.ltoreq.35.degree. C. and reactor jacket temperature
.ltoreq.45.degree. C. to yield the crude title product.
Method D
[0327] To a jacketed laboratory reactor is charged
1-({[(4-methoxycarbonylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
2-10; 10.80 g) and tert-butyl methyl ether (20 ml). Pregabalin
(7.35 g), water (20 ml) and acetonitrile (15 ml) are added and the
mixture is stirred for .about.10 minutes at 10-20.degree. C.
Triethylamine (6.2 ml) is charged over .about.5 minutes. The
reaction is stirred at 10-20.degree. C. for 5 hrs. 10% potassium
hydrogensulfate aqueous solution (67 ml) is charged to acidify
reaction to pH 4-4.5. Tert-butyl methyl ether (80 ml) is charged
and mixed for .about.10 minutes. After removal of aq. layer, the
organic layer is washed with water (50 ml). The solvents are
stripped off under reduced pressure with process temperature
.ltoreq.35.degree. C. and reactor jacket temperature
.ltoreq.45.degree. C. to yield the crude title product.
Method E
[0328] To a jacketed laboratory reactor is charged
1-({[(3,4-methylenedioxyphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
2-13; 10.50 g) and tert-butyl methyl ether (20 ml). Pregabalin
(7.35 g), water (20 ml) and acetonitrile (15 ml) are added and the
mixture is stirred for .about.10 minutes at 10-20.degree. C.
Triethylamine (6.2 ml) is charged over .about.5 minutes. The
reaction is stirred at 10-20.degree. C. for 5 hrs. 10% potassium
hydrogensulfate aqueous solution (67 ml) is charged to acidify
reaction to pH 4-4.5. Tert-butyl methyl ether (80 ml) is charged
and mixed for .about.10 minutes. After removal of aq. layer, the
organic layer is washed with water (50 ml). The solvents are
stripped off under reduced pressure with process temperature
.ltoreq.35.degree. C. and reactor jacket temperature
.ltoreq.45.degree. C. to yield the crude title product.
Example 3
3(S)-{[(1R)-1-(2-methylpropanoyloxyethoxy)carbonyl]aminomethyl}-5-methylhe-
xanoic acid (F2)
##STR00066##
[0329] Method A
[0330] The compound is prepared following the method described in
Example 2 (Method A) and reacting
1(R)-({[(2-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate
(may be prepared as described in Description 3-1) and
pregabalin.
Method B
[0331] The compound is prepared following the method described in
Example 2 (Method B) and reacting
1(R)-({[(3-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropano ate
(may be prepared as described in Description 3-3) and
pregabalin.
Method C
[0332] The compound is prepared following the method described in
Example 2 (Method C) and reacting
1(R)-({[(4-trifluoromethylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
3-13) and pregabalin.
Method D
[0333] The compound is prepared following the method described in
Example 2 (Method D) and reacting
1(R)-({[(4-methoxyphenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate
(may be prepared as described in Description 3-11) and
pregabalin.
Method E
[0334] The compound is prepared following the method described in
Example 2 (Method E) and reacting 1(R)-({[(3,4-methylenedioxy
phenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate (may be prepared
as described in Description 3-15 and pregabalin.
Example 4
4-{[(.alpha.-Isobutanoyloxyl-.beta.-methylpropoxy)carbonyl]amino}-3
(R)-(4-chlorophenyl)butanoic acid (G1)
##STR00067##
[0335] Method A
[0336] To a jacketed laboratory reactor is charged
1-({[(2-fluorophenyl)oxy]carbonyl}oxy)-2-methylproyl
2-methylpropanoate (may be prepared by following an analogous
method described for D2-1 and using the appropriate reagents; 20.0
g) in heptanes solution (40 ml). R-Baclofen (14.75 g), water (40
ml) and acetonitrile (30 ml) are charged and the mixture is stirred
for .about.10 minutes at 10-20.degree. C. Triethylamine (11.4 ml)
is added over .about.5 minutes. The reaction is stirred at
10-20.degree. C. for 4-8 hrs until
1-({[(2-fluorophenyl)oxy]carbonyl}oxy)-2-methylpropyl
2-methylpropanoate is <2% by HPLC. 2 M H.sub.2SO.sub.4 aqueous
solution (20 ml) is charged to acidify reaction to pH 4-4.5.
Tert-butyl methyl ether (90 ml) is charged and mixed for .about.10
minutes. After removal of the aqueous layer, the organic layer is
washed with water (30 ml). The solvents are stripped off under
reduced pressure with process temperature .ltoreq.35.degree. C. and
reactor jacket temperature .ltoreq.45.degree. C. to yield the title
product.
Method B
[0337] To a jacketed laboratory reactor is charged
1-({[(3-fluorophenyl)oxy]carbonyl}oxy)-2-methylpropyl
2-methylpropanoate (may be prepared by following an analogous
method described for D2-2 and using the appropriate reagents; 12 g)
and tert-butyl methyl ether (20 ml). R-Baclofen (7.35 g), water (20
ml) and acetonitrile (15 ml) are added and the mixture is stirred
for .about.10 minutes at 10-20.degree. C. Triethylamine (6.2 ml) is
charged over .about.5 minutes. The reaction is stirred at
10-20.degree. C. for 5 hrs. 10% potassium hydrogensulfate aqueous
solution (67 ml) is charged to acidify reaction to pH 4-4.5.
Tert-butyl methyl ether (80 ml) is charged and mixed for .about.10
minutes. After removal of the aqueous layer, the organic layer is
washed with water (50 ml). The solvents are stripped off under
reduced pressure with process temperature .ltoreq.35.degree. C. and
reactor jacket temperature .ltoreq.45.degree. C. to yield the crude
title product.
Method C
[0338] To a jacketed laboratory reactor is charged
1-({[(4-methoxycarbonylphenyl)oxy]carbonyl}oxy)-2-methylproyl
2-methylpropanoate (may be prepared by following an analogous
method described for D2-10 and using the appropriate reagents; 20.0
g) in heptanes solution (40 ml). R-Baclofen (14.75 g), water (40
ml) and acetonitrile (30 ml) are charged and the mixture is stirred
for .about.10 minutes at 10-20.degree. C. Triethylamine (11.4 ml)
is added over .about.5 minutes. The reaction is stirred at
10-20.degree. C. for 4-8 hrs until
1-({[(2-fluorophenyl)oxy]carbonyl}oxy)-2-methylpropyl
2-methylpropanoate is <2% by HPLC. 2 M H.sub.2SO.sub.4 aqueous
solution (20 ml) is charged to acidify reaction to pH 4-4.5.
Tert-butyl methyl ether (90 ml) is charged and mixed for .about.10
minutes. After removal of the aqueous layer, the organic layer is
washed with water (30 ml). The solvents are stripped off under
reduced pressure with process temperature .ltoreq.35.degree. C. and
reactor jacket temperature .ltoreq.45.degree. C. to yield the title
product.
Example 5
4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)carbonyl]amino}-3(R)-(4-chloroph-
enyl)butanoic acid (G2)
##STR00068##
[0339] Method A
[0340] The compound is prepared following the method described in
Example 4 (Method A) and reacting
1(S)-({[(2-fluorophenyl)oxy]carbonyl}oxy)-2-methylpropyl
2-methylpropanoate (may be prepared as described in Description
3-17) and R-baclofen.
Method B
[0341] The compound is prepared following the method described in
Example 4 (Method B) and reacting
1(S)-({[(3-fluorophenyl)oxy]carbonyl}oxy)-2-methylpropyl
2-methylpropanoate (may be prepared as described in Description
3-19) and R-baclofen.
Method C
[0342] The compound is prepared following the method described in
Example 4 (Method C) and reacting
1(S)-({[(4-methoxyphenyl)oxy]carbonyl}oxy)-2-methylpropyl
2-methylpropanoate (may be prepared as described in Description
3-27) and R-baclofen.
Example 6
4-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]amino}-3(R)-(4-fluorophenyl)but-
anoic acid (H1)
##STR00069##
[0343] Method A
[0344] To a jacketed laboratory reactor is charged
1-({[(2-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate (may
be prepared as described in Description 2-1; 20.0 g) in heptanes
solution (40 ml). 4-Amino-3-(4-fluorophenyl)butanoic acid (14.00
g), water (40 ml) and acetonitrile (30 ml) are charged and the
mixture is stirred for 10 minutes at 10-20.degree. C. Triethylamine
(11.4 ml) is added over .about.5 minutes. The reaction is stirred
at 10-20.degree. C. for 4-8 hrs until
1-({[(2-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate is
<2% by HPLC. 2 M H.sub.2SO.sub.4 aqueous solution (20 ml) is
charged to acidify reaction to pH 4-4.5. Tert-butyl methyl ether
(90 ml) is charged and mixed for .about.10 minutes. After removal
of aq. layer, the organic layer is washed with water (30 ml). The
solvents are stripped off under reduced pressure with process
temperature .ltoreq.35.degree. C. and reactor jacket temperature
.ltoreq.45.degree. C. to yield the title product.
Method B
[0345] To a jacketed laboratory reactor is charged
1-({[(3-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate (may
be prepared as described in Description 2-2; 10.06 g) and
tert-butyl methyl ether (20 ml). 4-Amino-3-(4-fluorophenyl)butanoic
acid (8.30 g), water (20 ml) and acetonitrile (15 ml) are added and
the mixture is stirred for .about.10 minutes at 10-20.degree. C.
Triethylamine (6.2 ml) is charged over 5 minutes. The reaction is
stirred at 10-20.degree. C. for 5 hrs. 10% potassium
hydrogensulfate aqueous solution (67 ml) is charged to acidify
reaction to pH 4-4.5. Tert-butyl methyl ether (80 ml) is charged
and mixed for .about.10 minutes. After removal of aq. layer, the
organic layer is washed with water (50 ml). The solvents are
stripped off under reduced pressure with process temperature
.ltoreq.35.degree. C. and reactor jacket temperature
.ltoreq.45.degree. C. to yield the crude title product.
Method C
[0346] To a jacketed laboratory reactor is charged
1-({[(4-trifluoromethylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
2-9; 10.80 g) and tert-butyl methyl ether (20 ml).
4-Amino-3-(4-fluorophenyl)butanoic acid (8.30 g), water (20 ml) and
acetonitrile (15 ml) are added and the mixture is stirred for
.about.10 minutes at 10-20.degree. C. Triethylamine (6.2 ml) is
charged over 5 minutes. The reaction is stirred at 10-20.degree. C.
for 5 hrs. 10% potassium hydrogensulfate aqueous solution (67 ml)
is charged to acidify reaction to pH 4-4.5. Tert-butyl methyl ether
(80 ml) is charged and mixed for .about.10 minutes. After removal
of aq. layer, the organic layer is washed with water (50 ml). The
solvents are stripped off under reduced pressure with process
temperature .ltoreq.35.degree. C. and reactor jacket temperature
.ltoreq.45.degree. C. to yield the crude title product.
Method D
[0347] To a jacketed laboratory reactor is charged
1-({[(4-methoxycarbonylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
2-10; 10.80 g) and tert-butyl methyl ether (20 ml).
4-Amino-3-(4-fluorophenyl)butanoic acid (8.30 g), water (20 ml) and
acetonitrile (15 ml) are added and the mixture is stirred for
.about.10 minutes at 10-20.degree. C. Triethylamine (6.2 ml) is
charged over 5 minutes. The reaction is stirred at 10-20.degree. C.
for 5 hrs. 10% potassium hydrogensulfate aqueous solution (67 ml)
is charged to acidify reaction to pH 4-4.5. Tert-butyl methyl ether
(80 ml) is charged and mixed for .about.10 minutes. After removal
of aq. layer, the organic layer is washed with water (50 ml). The
solvents are stripped off under reduced pressure with process
temperature .ltoreq.35.degree. C. and reactor jacket temperature
.ltoreq.45.degree. C. to yield the crude title product.
Method E
[0348] To a jacketed laboratory reactor is charged
1-({[(3,4-methylenedioxyphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
2-13; 10.50 g) and tert-butyl methyl ether (20 ml).
4-Amino-3-(4-fluorophenyl)butanoic acid (8.30 g), water (20 ml) and
acetonitrile (15 ml) are added and the mixture is stirred for
.about.10 minutes at 10-20.degree. C. Triethylamine (6.2 ml) is
charged over 5 minutes. The reaction is stirred at 10-20.degree. C.
for 5 hrs. 10% potassium hydrogensulfate aqueous solution (67 ml)
is charged to acidify reaction to pH 4-4.5. Tert-butyl methyl ether
(80 ml) is charged and mixed for .about.10 minutes. After removal
of aq. layer, the organic layer is washed with water (50 ml). The
solvents are stripped off under reduced pressure with process
temperature .ltoreq.35.degree. C. and reactor jacket temperature
.ltoreq.45.degree. C. to yield the crude title product.
Example 7
4-{[(1R)-1-(1-(2-methylpropanoyloxy)ethoxy]carbonylamino}-3(R)-(4-fluoroph-
enyl)butanoic acid (112)
##STR00070##
[0349] Method A
[0350] The compound is prepared following the method described in
Example 6 (Method A) and reacting
1(R)-({[(2-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate
(may be prepared as described in Description 3-1) and
4-amino-3-(4-fluorophenyl)butanoic acid.
Method B
[0351] The compound is prepared following the method described in
Example 6 (Method B) and reacting
1(R)-({[(3-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate
(may be prepared as described in Description 3-3) and
4-amino-3-(4-fluorophenyl)butanoic acid.
Method C
[0352] The compound is prepared following the method described in
Example 6 (Method C) and reacting
1(R)-({[(4-trifluoromethylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
3-13) and 4-amino-3-(4-fluorophenyl)butanoic acid.
Method D
[0353] The compound is prepared following the method described in
Example 6 (Method D) and reacting
1(R)-({[(4-methoxyphenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate
(may be prepared as described in Description 3-11) and
4-amino-3-(4-fluorophenyl)butanoic acid.
Method E
[0354] The compound is prepared following the method described in
Example 6 (Method E) and reacting 1(R)-({[(3,4-methylenedioxy
phenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate (may be prepared
as described in Description 3-15) and
4-amino-3-(4-fluorophenyl)butanoic acid.
Example 8
4-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-cyclohexanoic
acid (J1)
##STR00071##
[0355] Method A
[0356] To a jacketed laboratory reactor is charged
1-({[(2-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate (may
be prepared as described in Description 2-1; 20.0 g) in heptanes
solution (40 ml). Tranexamic acid (11.00 g), water (40 ml) and
acetonitrile (30 ml) are charged and the mixture is stirred for
.about.10 minutes at 10-20.degree. C. Triethylamine (11.4 ml) is
added over .about.5 minutes. The reaction is stirred at
10-20.degree. C. for 4-8 hrs until
1-({[(2-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate is
<2% by HPLC. 2 M H.sub.2SO.sub.4 aqueous solution (20 ml) is
charged to acidify reaction to pH 4-4.5. Tert-butyl methyl ether
(90 ml) is charged and mixed for .about.10 minutes. After removal
of aq. layer, the organic layer is washed with water (30 ml). The
solvents are stripped off under reduced pressure with process
temperature .ltoreq.35.degree. C. and reactor jacket temperature
.ltoreq.45.degree. C. to yield the title product.
Method B
[0357] To a jacketed laboratory reactor is charged
1-({[(3-fluorophenyl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate (may
be prepared as described in Description 2-2; 10.06 g) and
tert-butyl methyl ether (20 ml). Tranexamic acid (6.20 g), water
(20 ml) and acetonitrile (15 ml) are added and the mixture is
stirred for .about.10 minutes at 10-20.degree. C. Triethylamine
(6.2 ml) is charged over .about.5 minutes. The reaction is stirred
at 10-20.degree. C. for 5 hrs. 10% potassium hydrogensulfate
aqueous solution (67 ml) is charged to acidify reaction to pH
4-4.5. Tert-butyl methyl ether (80 ml) is charged and mixed for
.about.10 minutes. After removal of aq. layer, the organic layer is
washed with water (50 ml). The solvents are stripped off under
reduced pressure with process temperature .ltoreq.35.degree. C. and
reactor jacket temperature .ltoreq.45.degree. C. to yield the crude
title product.
Method C
[0358] To a jacketed laboratory reactor is charged
1-({[(4-trifluoromethylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
2-9; 10.80 g) and tert-butyl methyl ether (20 ml). Tranexamic acid
(7.10 g), water (20 ml) and acetonitrile (15 ml) are added and the
mixture is stirred for 10 minutes at 10-20.degree. C. Triethylamine
(6.2 ml) is charged over .about.5 minutes. The reaction is stirred
at 10-20.degree. C. for 5 hrs. 10% potassium hydrogensulfate
aqueous solution (67 ml) is charged to acidify reaction to pH
4-4.5. Tert-butyl methyl ether (80 ml) is charged and mixed for 10
minutes. After removal of aq. layer, the organic layer is washed
with water (50 ml). The solvents are stripped off under reduced
pressure with process temperature .ltoreq.35.degree. C. and reactor
jacket temperature .ltoreq.45.degree. C. to yield the crude title
product.
Method D
[0359] To a jacketed laboratory reactor is charged
1-({[(4-methoxycarbonylphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
2-10; 10.80 g) and tert-butyl methyl ether (20 ml). Tranexamic acid
(6.80 g), water (20 ml) and acetonitrile (15 ml) are added and the
mixture is stirred for 10 minutes at 10-20.degree. C. Triethylamine
(6.2 ml) is charged over .about.5 minutes. The reaction is stirred
at 10-20.degree. C. for 5 hrs. 10% potassium hydrogensulfate
aqueous solution (67 ml) is charged to acidify reaction to pH
4-4.5. Tert-butyl methyl ether (80 ml) is charged and mixed for 10
minutes. After removal of aq. layer, the organic layer is washed
with water (50 ml). The solvents are stripped off under reduced
pressure with process temperature .ltoreq.35.degree. C. and reactor
jacket temperature .ltoreq.45.degree. C. to yield the crude title
product.
Method E
[0360] To a jacketed laboratory reactor is charged
1-({[(3,4-methylenedioxyphenyl)oxy]carbonyl}oxy)ethyl
2-methylpropanoate (may be prepared as described in Description
2-13; 10.50 g) and tert-butyl methyl ether (20 ml). Tranexamic acid
(7.30 g), water (20 ml) and acetonitrile (15 ml) are added and the
mixture is stirred for 10 minutes at 10-20.degree. C. Triethylamine
(6.2 ml) is charged over .about.5 minutes. The reaction is stirred
at 10-20.degree. C. for 5 hrs. 10% potassium hydrogensulfate
aqueous solution (67 ml) is charged to acidify reaction to pH
4-4.5. Tert-butyl methyl ether (80 ml) is charged and mixed for 10
minutes. After removal of aq. layer, the organic layer is washed
with water (50 ml). The solvents are stripped off under reduced
pressure with process temperature .ltoreq.35.degree. C. and reactor
jacket temperature .ltoreq.45.degree. C. to yield the crude title
product.
[0361] From the foregoing description, various modifications and
changes in the compositions and methods provided herein will occur
to those skilled in the art. All such modifications coming within
the scope of the appended claims are intended to be included
therein.
[0362] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[0363] At least some of the chemical names of compounds of the
present disclosure as given and set forth in this application, may
have been generated on an automated basis by use of a commercially
available chemical naming software program, and have not been
independently verified. Representative programs performing this
function include the Lexichem naming tool sold by Open Eye
Software, Inc. and the Autonom Software tool sold by MDL, Inc. and
ChemDraw Ultra Version 10.0, available from CambridgeSoft.RTM.. In
the instance where the indicated chemical name and the depicted
structure differ, the depicted structure will control.
[0364] Chemical structures shown herein were prepared using
ISIS.RTM./DRAW or ChemDraw. Any open valency appearing on a carbon,
oxygen or nitrogen atom in the structures herein indicates the
presence of a hydrogen atom. Where a chiral center exists in a
structure but no specific stereochemistry is shown for the chiral
center, both enantiomers associated with the chiral structure are
encompassed by the structure.
* * * * *